CA2077412A1 - 1,2-dihydro-2-oxopyridines - Google Patents
1,2-dihydro-2-oxopyridinesInfo
- Publication number
- CA2077412A1 CA2077412A1 CA002077412A CA2077412A CA2077412A1 CA 2077412 A1 CA2077412 A1 CA 2077412A1 CA 002077412 A CA002077412 A CA 002077412A CA 2077412 A CA2077412 A CA 2077412A CA 2077412 A1 CA2077412 A1 CA 2077412A1
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- Prior art keywords
- alkyl
- dihydro
- butyl
- formula
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
Abstract New 1,2-dihydro-2-oxopyridines of formula I
I
in which R is the radical
I
in which R is the radical
Description
2 ~
~erck Patent Gesellschaft mit be8c~r~nkt~r ~atung 6100 D a r ~ ~ t a d ~
1,2-Dihydro-2-o~opyridi~es The invention relates to new 1,2-dihydro-2-oxopyridines of formula I
R-CH2 ~ -X ~ I
in which R i~ the radical Rs ¦ R3 R6 o 10 R1 i H, H~l, A, OA or NO2, R2 is CO~H, COOA, CN, NOz, NH2, NHCOR', NHSo2R7 or tetrazol-5-yl, R3 is H, COOH, COOA, CHO, CN, NO2, CH2R~, CH20R9, NRl0R11, CH2NR1DRll, CONRl0Rl1 or tetrazol-5-yl, 15 R~ is H or A, R , R
and R10 are in each ca~e H, A, alkenyl havin~
2-6 C atoms, alkynyl having 2-6 C atoms, Ar or Ar-al~yl having 1-6 C atoms in the "alkyl"
moiety, R~ is A or A monosubstituted or polysubstituted by F, ~7~
R~ i~ H, Hal, A, Ar, CN, COOH, COOA, CH2COOH, ~HzCOOA
or ~etrazol-5-yl, R~ is H, P~, Ar, Ar-alkyl having 1-6 C atoms in the "alkyl" moiety, CO~, COAr, C:OOA, COOAr, CoN~1-Rl3, COO-alkyl-Ar ~r A-O-alkyl having 1-6 C atoms in the ~ alkyl ~ moiety in each case, Rll is H, A, A monosub~tituted or polysubstitu~ed by F, Ar, Ar-alkyl having 1-6 C atoms in the ~alkyl~` moiety, CO-A, CO-Ar, CO-alkyl-Ar having O L-6 C atoms in the ~alkyl" moiety, COOA, COOAr, COO-alkyl-Ar having 1-6 C atomY in the "alkyl"
moiety, CONR1 2R1 ~, âO2R or SO2Ar, NRlRll is also pyrrolidino, piperidino, morpholino, suc-cin~ido or phthalimido, R12 and Rl3 are in each case H, A, cycloalkyl havîng 3-8 C
atoms/ alkenyl having 2-6 C atom~, alkyl~yl having 2-6 C atoms, or Ar, X is absent or is -CO-, -O-, -NH-CC)-, -CO-~
2 0 CH2~0 or -O-CH2-, A is alkyl ha~ing 1-6 C atom, Ar is phenyl which is unsub~tituted or monosub-stituted by A, GA, CF3, Hal or NO2, and Hal is F, Cl, Br or I, ~herein, ho~ever, at least one of the following provisos must b~ Ir~t:
(a) R~ is Hal, A, OA or NO2;
(b3 R2 is CN, NO2, NH2, NH~)R7 or NHSo2R7;
(c) R3 is GH2Ar, CH2CN, Cl~2COOH, CH2C(X)A, CH2CH2COOH, CH2CH2COOA, C~.-(tetrazol-5-yl);
CH~OAr, CH2~alkyl-Ar' (~herein Ar' is a phenyl group monosubstituted by A, OA, CF3, Hal or NO2), CH2~CO Ar', CH20COOAn, CH20CONRl4Rl5, (~herein Rt4 and R1s, independently fram each other9 are alkenyl, alkinyl or Ar, one of R14 and R1s can also be H or A), CH2~CO~alkyl-Ar, CH2~alkyl-O-A;
_ 3 _ 2 ~ 7 7 ~ ~ ~
NRl~RI7 (wherein Rl~ is alkenyl, alkinyl, Ar or Ar-alkyl, Rl~ is A monosubstituted or polysubstituted by F, Ar Ar-alkyl, CO-Ar, CO-alkyl-Ar, COOA, C~OAr, CCO-alkyl-Ar or CONRl2Rl3, one o~ Rl 6 and R17 can also be H or A), pyrro~idino, piperidino, morpholino, succinimido, phthalimido;
CH2NRloRl1;
CONRl8Rl9 (wherein Rl8 is alkenyl, alkinyl~
Ar or Ar-alkyl, Rl9 is A monosubstituted or polysubstituted by F, Ar'. Ar-alkyl, CO-Ar, CO-~lkylAr, COOA, COOAr, COO-alkyl-Ar or CONRl2Rl3, one of Rl~ and Rl~ can also be H or A, the group NR1~Rl9 can also be succinimido or phtha1imido);
(d) R5 is alkinyl, Ar' or Ar-alkyl;
~e) R~ is alkinyl, Ar' or Ar-alkyl;
(f) X is -CO-, -O-, -NH-CO-, -CO-NH-, -CH~-C- or -C-CH2-, -~ and their salt~.
Similar compounds ara ~nown fr~m EP-A2-400974 and US-A1 4 880 804 and wO91~19697.
The object of the invention wa~ to find ~ovel compound~ with valuable properties, especi~lly those which can be ~sed fo~ the preparati~n of drugs.
It wa~ found that the compounds of formula I and their salt~ po~ ess very ~aluable pharmacological properties coupled with a good tolerance. In particular, they have antagonis~ic properties towards angiotensin II
and can therefore be used for the trea~ment of angio-tensin II-dependent hyperten~ion, aldoste~onism and cardiac insufficiency~ These effects can be determined 2B77~
by conventional in vitro or in vivo m~thods such as, for example, those described in US patent 4 880 804 and also by A.~. Chiu et al., J. Pharmacol. Expo Therap. 250, 867-~74 (1989)~ and by P.C. Wong et al.~ ibid. 252, 719-S 725 ~1990; ~n ~ivo, on rats).
The compounds of formula I can be used as phar-maceutical active ingredients in human and veterinary medicine, ~specially for the prophylaxis and/or therapy of cardiac, circulatory and vascular disease~, in particular of hypertonia, cardiac insufficiency and hyperaldosteronism.
The invention relates to th~ compounds of formula I and their salt~ and to a process for the preparation of these compounds and their salts, characterised in that (a) a compound of formula II:
E-CH2 ~ -X ~ Rl II
in which ~ i5 Cl, Br, I, a free OH group or an OH group which ha~ b~en functlonally modified to acquire reactivity, and Rl, R2 and ~ are a~ defined in Cla.~m 1, is reacted with a compound of formula III:
H-R III
in which R is as defined in ClaLm 1, or (b) to prepare a compound of formula I in which X is -NH-CO- or -CO-NH-, a compound of formula IV:
_ 5 _ 2~7 ~
f=~
R-CH2 ~ Xl IV
in which ~1 iS NH2 or COOH and R is as defined in Claim I/
or a reactive derivative of this compound, is reacted with a compound of formula V:
~= ~ Rl X2~ V
in which x2 is COOH (if Xl is NHz) or NH2 (if Xl is COO~) and Rl and R2 are as def ined in Claim 1~
or with a reac~ive derivative of this compound, or (c) to prepare a compound of fo~nula I in which ~ is -C~2-- ~ --~2- / a compound of formula VI:
R-CH2 ~ -X3 VI
in which X3 is CH2E or O~ and R i~ as defined in Claim 1, or a reactive derivative of this compound, is reacted with a coMpound of fo~nula VII:
,, 2 1~
Rl X~ ~ VII
in which X4 is OH (if X3 is CH2E) or CH2E (if X3 is OH) and R1 and R2 are as defined in Claim 1, or with a reactive derivative of thi~ compound, or in that a compound of formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent, and/or in that one or more radicals R1, R2, R3, R~, R5 and/or R6 in a compound of formula I are converted to one o~ more other radicals R , R , R , R , R and/or R , and~or a ba~e or acid of formula I i3 con~erted to one of itR
sal~s.
Above and below, unle~ expressly indicated otherwi~e, the radicals or parame~ers R, Rl to Rl3, X~ A, Ar~ Hal, E, ~ 2~ X3 and X4 are as defined in formulae I to VII.
In the above formulae, A hax 1-6, preferably 1, 2, 3 or 4 C atom~. A is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ~ec-butyl or tert-butyl, or el~e pentyl, 1 ~ 2- or 3 methylbutyl, 1,1-, ~ or 2,2-dLmethylpropyl, l-ethylpropyl, hexyl, 1-, 2-, 3 or 4-methylpentyl, 1,1~, 1,2-, 1,3-, ~,2~, 2,3-or 3,3-dimethylbutyl, 1~ or 2-ethylbutyl, l-ethyl-1-25 methylpropyl, l ethyl-2 methylpropyl or 1,1,2 or 1,2,2-trLm~thylpropyl.
Ar i~ preferably unsubstituted phenyl, or else preferably o-, m- or p-tolyl, o , m- or p-ethylphenyl, o-, m- or p-i~opropylphenyl, o-, m- or p-me~ho~yphenyl, 30 o-, m- or p-etho~yphenyl, o-, m- or p-i~opropoxyphenyl, o , m- or p-trifluoromethylphenyl, o-, m or p-fluoro-phenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl or o-, m- or p~nitrophenyl.
- 7 -- 20~
Hal is preferably F, Cl or Br, or else I.
Alkenyl has 2-6, preferably 2, 3 or 4 C a~o~s and is preferably vinyl, allyl, prop-l-en-l-yl, prop-1-en-2-yl, but~l-, -2- or -3-en-1-yl or but-l~, 2- or -3-en-2-yl.
Alkynyl has 2 6, preferably 2, 3 or 4 C atoms and is pr~ferably ethynyl, prop-l- or -3-yn-1-yl or but-1-, -2- or ~3-yn-1-yl.
In Ar-alkyl the ~alkyl'~ moiety has 1-6, pre-ferably 1, 2 or 3 C atom3. Ar-alkyl is preferably benzyl, 1- or 2-phenylethyl or 1-, 2- or 3 phenylpropyl~
or else preferably o-, m- or p-methylbenzyl, o, m- or p-methoxybenzyl, o-, m- or p-trifluoxomethylbenzyl, o-, m-or p-fluorobenzyl, o-, m- or p-chlorobenzyl, o-, m- or p-bromobenzyl or o-, m or p-nitrobenzyl.
~ 'A substituted by F" is preferably CH2F, CHY2, CF3, CH~-CF3, CF2-CF3, CH2-CH~-CF3, CH2-~2-CF3~ C3F7~ t~F3)2CH
or iso-C3F7.
Cycloalkyl has 3-8, preferably 3, 4, 5 or 6 C
~0 atom~ and i~ pxeferably cyclopropyl, cyclobutyl, cyclo-pentyl or cyclohexyl.
The radicals Rl, R4 and R5 are preferably H in each case, or else preferably A in each ca~e.
The radical R3 is preferably H, CH20R9 (especially CH20A such as methoxymethyl, ethoxymethyl! propoxymethyl, isopropoxymethyl, buto~ymethyl, i~obutoxymethyl, pentoxy-methyl or hexyloxymethyl; or CH20-alkyl-Ar such as ben-zyloxymethyl), CH2RlRll (especially CH2~HRll, in particular CH2NHA such as methyl~minomethyl, ethyl~minomethyl, propylaminomethyl, isopropylaminomethyl, butylamino-methyl, isobutylaminomethyl, pentylaminomethyl or hexyl-aminomethyl; CH2NH-alkyl-Ar such as benzylaminomethyl; or CH2NA-CO-NHAr such as N-methyl-N'-phenylureidomethyl, N-ethyl-N'-phenylureidomethyl, N-propyl-N'-phenylureido-methyl, N-isopropyl-N'-phenylureidomethyl, N-butyl-N'-phenylureidomethyl, N-isobutyl-N'-phenylureidomethyl t N-pentyl-N'-phenylureidome~hyl or N-hexyl-N'-phenyl-ureidomethyl) or tetrazol-5-yl. R3 is also preferably - 8 - 2~P~
COO~ (~specialIy methoxycarbonyl or ethoxycarbonyl), CHO, CN, CH2R~ (especially A such as methyl or ethyl) or CONRlQRll such as CONH2.
very particularly preferred radicals R3 are H or tetrazol-5-yl, or else butoxym~thyl, benzyloxymethyl, butylaminomethyl, benzyla~inomethyl and N-butyl-N~-phenylureidomethyl.
The radical R3is preferably linear and is prefer-ably A or alkenyl having 3-6 C atoms in each case, especially butyl, or else propyl, pentyl, hexyl, allyl or prop-1-enyl, or else but-l-enyl, pent-1-enyl, hex-l-enyl, prop-l-ynyl, but-l-ynyl, pent-1-ynyl or hex-l-ynyl.
The radical R7 is preferably A, especially methyl (~ or ethyl, or CF3.
The radi~al R8 i8 preferably ~, F, Cl, A, CN, COOH, COOA or tetrazol-5-yl.
The radical R9 is preferably H, A (especially having 3-5 C atoms) or benzyl.
The radical Rl is preferably H, A or benzyl.
The radical Rl iS preferably ~, ~ (especially having 1-5 C atoms), A polysubstituted by F, benzyl, CO-A, CO-Ar, CO-CH2C6H5, COOA, COOAr, COOCH2CsHs, CONH2, CONHA, CONH-cycloalkyll CONA2 or CONHAr.
The radical ~ is preferably absent or is pre-ferably -NH-CO- or -CO-NH-~
The compound3 of formula I can possess one or more chiral cen~res and can ther~fore exist in different forms (optically active or optically inactive). Formula I includes all the~e forms.
Accordingly, the invention relates especially to those compounds ~f formula I in which at least one of said radicals has one of the preferred meanings indicated above. Some preferred yroups of compounds can be expressed by the following partial formulae Ia to Ig, which correspond to formula I and in which the radicals not described more precisely are as defined in formula I, except that in Ia: R3 is H;
2 0 7 ~
in Ib: R-'is COOH~ COOA or CONRlR~l;
in Ic: R3is CHO or CN;
in Id~ R is CH2R~;
in Ie: R3is CH20R8;
5 in If R3is NRl~Rl~ or C~ NRlRll; and in Ig: R is tetrazol-5-yl.
Particularly preferred compounds are those of formulae Ih and Iah to Igh, which correspond to formulae I and Ia to Ig except that in addition X is absent.
Other preferred compounds are those of formulae Ii and Iai to Igi, which correspond to formulae I and Ia to Ig excep~ that in addition X is -CO-.
Other preferred compounds are those of formulae I~ and Iaj to Igj, which correspond to formulae I and Ia to Ig except that in addition X is -O-.
Other preferred compounds are those of formulae Ik and Iak to Igk, which correspond to formulae I and Ia to Ig except that in addition X is -NH-CO-.
Other preferred compounds are those of formulae Il and Ial to Igl, which correspond ~o formulae I and Ia to Ig except ~ha~ in addition X is -CO-NH-.
Other preferred compound~ are those of formulae Im and Iam to Igm, which correspond to for~ulae I and Ia to Ig except that in addition X i~ -CH2-O-.
Other preferred compounds are those of formulae In and Ian to Ign, ~hich correspond to formul~e I and Ia to Ig except that in addition X i~ -O-CH2-.
Particularly preferred compounds are those of formulae I, Ia to In and Iah to Ign in which in addi~ion R1 is H and/or R~ and/or R5 are H or A and~or R6 is A
(especially propyll butyl or pentyl).
Among these, preferred compounds are those in which R2 i~ COOH, COOCH3, COOC2Hs, C~ or tetrazol-S-yl.
A v~ry particularly preferred group of compounds i8 that of formula I in which Rl is H, R2 i8 COOH, COOA, CN or tetra~ol-S-yl, 2~7~
1 o --R3 is H~ C~20~, CH20CH2~6H5, CH2N~A, CH~NHCH2C6H5, CH2.~ACONHC6H5 or tetrazol-S-yl~
R' and R3 are H or A in each case, 5 R~ is A and X is absen~.
A small selected group of preferred compounds is that of formula I in which R, R
10 and R5 are H in each case, R2 is CN or tetrazol-5-yl, R3 is H, CH20-alkyl having 3-5 C atoms in the alkyl group, or tetrazol-5-yl, R6 is al~yl having 3-5 ~ atoms and 15 X is abs~nt.
The compound~ of formula I and al~o the starting material~ for their prepara~ion are moreov~r prepared by methods known per se~ such as those described in ~he literature ~or ~xampl~ in the ~tandard works like Houben-Weyl, ~ethoden der organischen Chemie (Methods of Organic Chemi3try~, Georg-Thieme-V~rlag~ Stuttgart, but especially US patent 4 880 804), under reaction condi-tions which are known and suitable for ~aid reaction~, it also bein~ possibl~ to make use of variants known per se~
which are not ~entioned in greater detail here.
If desired, the starting materials can al~o be formed in situ, ~o that they are not isolated from thc reaction mixture but immediately reacted further to give the compo~lnds of formula I.
The compound~ of formula I can preferably be obtained by reacting compounds of formula II with com-pounds of fonmula III. Particularly the biphenyl deriva~
~ives of formula I (in which X i~ absent~ are readily obtainable in this way.
1 1 2077~ 3 In the compound~ of formula II~ E is preferably Cl, Br, I or an OH group which has been ~unctionally modified to acquire reac~ivity~ such a~ al ~lsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) or S arylsulfonylo~y having 6-10 C atoms (preferably phenyl-or p-tolyl-sulfonyloxy).
The reaction of II with III is conveniently carried out by first converting III to a salt by treat-ment with a base, f or example with an alkali metal alcoholate such as C~30Na in an alcohol ~uch as CH30H, or with NaH or pota~sium tert-butylate in dimethylformamide (DMF), and then reacting said salt with II in an inert solvent, for example an amide such as DMF or dimethyl acetamide, or a sulfoxide such as dLmethyl sulfoxide (DMSO), conveniently at temperature~ of between -20 and 00 D ~ pref~ra~ly of between 10 and 30.
Acid amides of formula I (X = -~H CO- or -CO-NH-) can also be obtained by reacting compound~ of formula IV
50r reactive d~ri~ative~ thereof) wi~h oompounds of formula V (or reactive derivative~ thereof). Suitable reactive derivative~ cf the carboxylic acid~ of formulae IV and V ~Xl or X~ = COOH~ are advanta~eously the corresponding chloride~, bromides or anhydrides. Th~
reaction is conveni~ntly ~Arried out in the presence of ~5 an inert ~olvent, for example a halogenated hydrocarbon such as methylene chloride, chloroform, tri~hloroethene or 1,2-dichloroe~hane, or an ether such as tetrahydro-furan (THF) or dioxane~ at temperatures of between O and 150, preferably of between 20 and 80. If acid halides are reacted, it is recommended to add a base, for example a tertiary amine such a~ triethylamine, pyridine or 4-dLmethylaminopyridine.
Ethers of formula I (X = -CH2-O~ or -O-C~2-) can be obtained by reacting compounds of formulae VI and VII
(or reactive derivatives thereof). Examples of suitable reactive derivatives of the phenol3 VI and VII (X3 or X4 = OH) are the corresponding alkali metal (for example Na, ~ phenolate~l which can al~o be formed in situ from the phenol and a has2 ~for example potassium carbonate). ~h~
reaction is conveniently carried out in the presence of an inert solvent, for example an amide such as DMF or a sulfoxide such as DMSO, at temperatures of between 0 and l50~, preferably of between 20 and l00.
Some of the starting materials of formulae II, III, IY, V, VI and VII are known. If they are not known, they can be prepared by known methods analogously to known substances. Compounds of formula II are extensive-10 ly known (compare, for example, EP-A2-400974~. Compounds of formula III can be obtained for example by reacting ketones of the formula R6-Co-CH2-R5 (preferably R~-CO-CH3) with esters of the formula R4-CooA (preferably HCOOA, especially HCOOC2H5) to give dicarbonyl compounds of the formula R6_co-c~5=cR4-oH (preferably R6-CO-CH=CH-O~;
"enolone form~') and then conden~ing these with aceta~ide3 of the formula R3-CH2 CON~2, especially cyanoaceta~ide.
It is thus possible in particular to obtain 3-cyano-4-R4-S-Rs-6-R6-l t 2-dihydro-2-oxopyridines (for~ula XII, ~0 R3 = CN, R4 = R5 = H), for example 6-butyl-3 cyano-l,2-dihydro-2-oxopy~idine ("IIIb"). The f~llowing are examples of compounds which can be ob~ained from these 3-cyano compounds: by hydrolysis (for example with hydro-chloric acid), the carboxylic acids (III, R3 = COOH); from these, by esterification ( for example with an alcohol A-OH in the presence of a strong acid), the esters (III, R3 = COOA~; by decarboxylation, the l,2-dihydxo 2-oxopyridines unsubstituted in the 3-position lIII, R3 = H); by reduction, the 3-hydroxymethyl compounds (III, R3 = CH20H) or the 3-aminomethyl compound~ tIII, R3 = CH2NH2l; and by oxidation of the latter, for example with ~nO2, the aldehydes (III, R3 = CHO), which can al~o be prepared from the nitriles by reaction with diiso-butylaluminium hydride. Partial hydrolysis of the 35 nitriles (III, R3 = C~; for example with 90~ H2SO4;
compare US-Al-4 137 233) gives the carboxamides (III, R3 = CONH2), which can be degraded with NaOH/sr2 to the 3-amino compounds (III, R3 = NH2) (compare -- 13 - ~7 US-A-l~ 13~ 233).
To convert a radical R3 in ~tarting materials of formula III, it i5 al50 possible to block the 2-oxo group as an interm~diate step. Thus, for e~ample, nitriles (III, R3 = CN) can be converted to the corresponding 2 ben~yloxy-3-cyano-4-R4-5-R~-6-R6-pyridines with benzyl chloride/AgzO in boiling toluene; the corresponding 3-carboxylic acids can be ob~ained from these ~y boiling with ethanolic ROH and the corresponding 3-hydroxymethyl compounds can be obtained by reducing said acids.
Alkylation, for example with iodides of the formula A-I, gives the corresponding 2-benzyloxy-3-alkoxymethyl-4-R4-5-R5-6-Rs-pyridines, which can be hydrogenolysed to compounds of formula III (R3 = A-O-CH2~
A compound of formula I can also be liberated from one of its functional derivatives by treatment with a solvolysing Ifor example hydrolysing) or hydrogeno-ly~ing agent.
It is thus possible, using one of the indicated methods, to prepare a compound which has formula I but in which the ~etragol-5-yl group is replaced with a tetrazol-S-yl group functionally modified in the l-position (pro~ected by a protecting group). Examples of suitable prote~ting groups are: triphenyl~ethyl, which can be cleaved with HCl in an inert solvent or solvent mixture~ for example ether/methylene chloride/methanol;
2-cyanoethyl, which can be cleaved with NaOH in wa~er/THF; and p nitrobenzyl, which can be cleaved with ~2/Raney nickel in ethanol (compare EP-A2-0 291 969).
It is also possible to conver~ one compound of formula I to another compound of formula I by converting one or more of the radicals R1, R2, R3, R4, R5 and/or R6 to other radical~ Rl, R2, R3, R4, R5 and/or R6, for example by reducing nitro group~ to amino groups (for example by hydrogenation on Raney nickel in an inert solvent such as methanol or ethanol), and/or functionally modifying free mino and~or hydroxyl groups, and/or liberating functionally modified amino and/or hydroxyl groups by -- 1 A _ 2 0 7 7 ~1 1 r l solvolysis or hydro~enolysis~ and~or replacing halogen atoms with OA or CN groups (for example by reaction with alkali metal alcoholates or with copper(I) cyanide~, and/or hyd.rolysing ni~rile groups to CONH2 or COOH groups, or converting nitrile groups to tetrazolyl groups with hydrazoic acid deriva~ives, andtor reducinq CHO groups to CH20H groups (for example with NaBH4), or converting CHO
groups to aminomethyl, A-NH-CH2 or Ar-alkyl-NH-CH2 group~
( f or examp~ e ~ith ammonia or prLmary amines in the presence of a reducing agent such as NaCNBH3), and/or degrading CONH2 groups to NH2 groups (for example with Br2/ aqueous NaOH solution).
Thus, for example, free hydroxyl and~or amino qroups can be acylated in a conventional manner with an acid chloride or anhydride, or alkylated with an alkyl or aralkyl chloride or bromide, conveniently in an inert solvent such as methylene chloride or THF, and/or in the presence of a base such as triethylamine or pyridine, at temperature~ of between -60 and +30. The conversion of prLmary amino groups to secondary or tertiary amino group~ is al~o effected by reaction with appropriate aldehydes or ketones in the presence of a reducing agent.
If desired, a functionally modified amino and~or hydroxyl group in a compound o~ formula I can be liberated by solvolysis or hydrogenolysis using conven-tional methods. Thus, for example, a compound of formula I containing an NHCoR7 ~ NHCOOA or AOOC group can be converted ~o the corresponding compound of formula I
containing an NH2 or H~OC group instead. AOOC groups can be ~aponified for example with NaOH or KOH in water, water/THF or water/dioxane at temperature~ of between O
and 100 9 .
The reaction of nitriles of formula I (R2 and/or R3 = CN) with hydrazoic acid derivative~ gives tetrazoles of formula I ~R2 and/or R3 = tetrazol-5-yl). It iæ
pref~rable to use trialkyltin azides such as trLmethyltin azide, in an inert ~olvent, for example sn aromatic hydrocarbon such as toluene, at temperatures of between ~r ~77~
20 and 15Q~, preferably of between 80 and 140, or sodi~m a~ide in N-methylpyrrolidone at temperatures of between about 100 and 200.
A base of formula I can be converted with an acid to the corresponding acid addition salt. Possible acids for this reaction are especially those which yield physiologically acceptable salts. Thus it is pos~ible to use inorganic acids, for exampl~ sulfuric a~id, nitric acid, hydrohalic acids such as hydrochloric acid or lQ hydrobromic acid, phosphoric acid~ such as orthophos-phoric acid, and sulfamic acid, as well as organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pi~alic acid, diethylacetic acid, mal~nic acid, succinic acid, pLmelic acid, fuma~ic a~id, maleic acid, lactic acid, tartaric acid, malic acid, ~itric acid, gluconi~ acid, ascorbic acid, nicotinic acid~
isonicotinic acid, meth~ne- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzene~ulfonic acid, p-toluene~ulfonic acid, naphtha-lene-monosulf OniG and -di~ulfonic acid~ and lauryl-sulfuric acid. Salt~ with phy~iologically unacceptable acids, for example picrate~, can be used for isolating and/or purifying the compound~ of formula I.
On the other hand, compounds of formula I con-taining COOH or tetrazolyl groups can be converted with bases (for sxample sodium or pota~sium hydroxide or carbonatej to the corresponding metal saltQ, especially alkali metal or alkaline earth metal salts, or to the corresponding ammonium salts. The potassium sal~ of the tetrazolyl derivative~ are particularly pref erred .
The novel compounds of formula I and thair phy~iologically acceptable salt~ can be used for the 35 manufacture of pharmaceutical preparations by incorpora-tion into a ~uitable dosage form together with at least one excipient or ad~unct and, if de~ired, together with one or more other active inyredients. The re~ulting 2~77`~
~ lh -formulations can be used as drugs in human or veterinary medicinP. Possible excipients are organic or inorganic substances which are suitable for enteral ~for example oral or rectal) or parenteral administration or for adminis~ration in the form of an inhalation spray, and which do not react with the novel compounds, for example water, vegetable oil~, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycer-ides, gelatin, ~oya lecithin, carbohydrates such as lactoRe or starch, magnesiu~ stearate, talc and cellulose. Tablets, coated tablets, capsules, syrups, juices or drops, in particular, are used for oral admini-stration; film-coated tablet~ and capsule~ with coatings or shells resistant to gastric ~uice are of special interest. Suppositorie5 are used for rectal admini-~tration and solution~, preferably oily or aqueou~
solutions, as well as ~uspensions, emulsinns or Lmplants, are u~ed for parenteral administration. For admini-stration as inhalation spray~, it i8 possible to us~
sprayq containing tha active ingredient either di ~olved or ~u~pended in a propollant mixture (f~r e~a~ple chloro_ fluorocarbons). It is con~enient here to use the acti~e ingredient in micronised form, it being possible for one or more additio~al physioloqically compatible solvents, 25 for example ethanol, to be present. Inhalation solutions can be admini~ered with the aid of conventional inhalers. The novel compou~d~ can also be lyophilised ~nd the resulting lyophili~ate~ used for example for the manufacture of in~ectable preparation~. The indicated form~lations can be ~t~rilised ~nd~or can contain ad~unct3 3uch as preservatives, stabili~ers and/or wetting agents, emulsifier~, salt~ for influencing the osmotic pre~ure, buffer ~ubstance and colorant~ andtor flavouring~. If desired, they can alRo contain one or more other acti~e ingredients, for example one or more vitamins, diuretic~ or antiphlogistics.
The sub~tances according to the invention are normally admini~ered analogously to other known, commercially ~vailable preparations, but in par~icular analogously to the compounds de~cribed in US paten~
~erck Patent Gesellschaft mit be8c~r~nkt~r ~atung 6100 D a r ~ ~ t a d ~
1,2-Dihydro-2-o~opyridi~es The invention relates to new 1,2-dihydro-2-oxopyridines of formula I
R-CH2 ~ -X ~ I
in which R i~ the radical Rs ¦ R3 R6 o 10 R1 i H, H~l, A, OA or NO2, R2 is CO~H, COOA, CN, NOz, NH2, NHCOR', NHSo2R7 or tetrazol-5-yl, R3 is H, COOH, COOA, CHO, CN, NO2, CH2R~, CH20R9, NRl0R11, CH2NR1DRll, CONRl0Rl1 or tetrazol-5-yl, 15 R~ is H or A, R , R
and R10 are in each ca~e H, A, alkenyl havin~
2-6 C atoms, alkynyl having 2-6 C atoms, Ar or Ar-al~yl having 1-6 C atoms in the "alkyl"
moiety, R~ is A or A monosubstituted or polysubstituted by F, ~7~
R~ i~ H, Hal, A, Ar, CN, COOH, COOA, CH2COOH, ~HzCOOA
or ~etrazol-5-yl, R~ is H, P~, Ar, Ar-alkyl having 1-6 C atoms in the "alkyl" moiety, CO~, COAr, C:OOA, COOAr, CoN~1-Rl3, COO-alkyl-Ar ~r A-O-alkyl having 1-6 C atoms in the ~ alkyl ~ moiety in each case, Rll is H, A, A monosub~tituted or polysubstitu~ed by F, Ar, Ar-alkyl having 1-6 C atoms in the ~alkyl~` moiety, CO-A, CO-Ar, CO-alkyl-Ar having O L-6 C atoms in the ~alkyl" moiety, COOA, COOAr, COO-alkyl-Ar having 1-6 C atomY in the "alkyl"
moiety, CONR1 2R1 ~, âO2R or SO2Ar, NRlRll is also pyrrolidino, piperidino, morpholino, suc-cin~ido or phthalimido, R12 and Rl3 are in each case H, A, cycloalkyl havîng 3-8 C
atoms/ alkenyl having 2-6 C atom~, alkyl~yl having 2-6 C atoms, or Ar, X is absent or is -CO-, -O-, -NH-CC)-, -CO-~
2 0 CH2~0 or -O-CH2-, A is alkyl ha~ing 1-6 C atom, Ar is phenyl which is unsub~tituted or monosub-stituted by A, GA, CF3, Hal or NO2, and Hal is F, Cl, Br or I, ~herein, ho~ever, at least one of the following provisos must b~ Ir~t:
(a) R~ is Hal, A, OA or NO2;
(b3 R2 is CN, NO2, NH2, NH~)R7 or NHSo2R7;
(c) R3 is GH2Ar, CH2CN, Cl~2COOH, CH2C(X)A, CH2CH2COOH, CH2CH2COOA, C~.-(tetrazol-5-yl);
CH~OAr, CH2~alkyl-Ar' (~herein Ar' is a phenyl group monosubstituted by A, OA, CF3, Hal or NO2), CH2~CO Ar', CH20COOAn, CH20CONRl4Rl5, (~herein Rt4 and R1s, independently fram each other9 are alkenyl, alkinyl or Ar, one of R14 and R1s can also be H or A), CH2~CO~alkyl-Ar, CH2~alkyl-O-A;
_ 3 _ 2 ~ 7 7 ~ ~ ~
NRl~RI7 (wherein Rl~ is alkenyl, alkinyl, Ar or Ar-alkyl, Rl~ is A monosubstituted or polysubstituted by F, Ar Ar-alkyl, CO-Ar, CO-alkyl-Ar, COOA, C~OAr, CCO-alkyl-Ar or CONRl2Rl3, one o~ Rl 6 and R17 can also be H or A), pyrro~idino, piperidino, morpholino, succinimido, phthalimido;
CH2NRloRl1;
CONRl8Rl9 (wherein Rl8 is alkenyl, alkinyl~
Ar or Ar-alkyl, Rl9 is A monosubstituted or polysubstituted by F, Ar'. Ar-alkyl, CO-Ar, CO-~lkylAr, COOA, COOAr, COO-alkyl-Ar or CONRl2Rl3, one of Rl~ and Rl~ can also be H or A, the group NR1~Rl9 can also be succinimido or phtha1imido);
(d) R5 is alkinyl, Ar' or Ar-alkyl;
~e) R~ is alkinyl, Ar' or Ar-alkyl;
(f) X is -CO-, -O-, -NH-CO-, -CO-NH-, -CH~-C- or -C-CH2-, -~ and their salt~.
Similar compounds ara ~nown fr~m EP-A2-400974 and US-A1 4 880 804 and wO91~19697.
The object of the invention wa~ to find ~ovel compound~ with valuable properties, especi~lly those which can be ~sed fo~ the preparati~n of drugs.
It wa~ found that the compounds of formula I and their salt~ po~ ess very ~aluable pharmacological properties coupled with a good tolerance. In particular, they have antagonis~ic properties towards angiotensin II
and can therefore be used for the trea~ment of angio-tensin II-dependent hyperten~ion, aldoste~onism and cardiac insufficiency~ These effects can be determined 2B77~
by conventional in vitro or in vivo m~thods such as, for example, those described in US patent 4 880 804 and also by A.~. Chiu et al., J. Pharmacol. Expo Therap. 250, 867-~74 (1989)~ and by P.C. Wong et al.~ ibid. 252, 719-S 725 ~1990; ~n ~ivo, on rats).
The compounds of formula I can be used as phar-maceutical active ingredients in human and veterinary medicine, ~specially for the prophylaxis and/or therapy of cardiac, circulatory and vascular disease~, in particular of hypertonia, cardiac insufficiency and hyperaldosteronism.
The invention relates to th~ compounds of formula I and their salt~ and to a process for the preparation of these compounds and their salts, characterised in that (a) a compound of formula II:
E-CH2 ~ -X ~ Rl II
in which ~ i5 Cl, Br, I, a free OH group or an OH group which ha~ b~en functlonally modified to acquire reactivity, and Rl, R2 and ~ are a~ defined in Cla.~m 1, is reacted with a compound of formula III:
H-R III
in which R is as defined in ClaLm 1, or (b) to prepare a compound of formula I in which X is -NH-CO- or -CO-NH-, a compound of formula IV:
_ 5 _ 2~7 ~
f=~
R-CH2 ~ Xl IV
in which ~1 iS NH2 or COOH and R is as defined in Claim I/
or a reactive derivative of this compound, is reacted with a compound of formula V:
~= ~ Rl X2~ V
in which x2 is COOH (if Xl is NHz) or NH2 (if Xl is COO~) and Rl and R2 are as def ined in Claim 1~
or with a reac~ive derivative of this compound, or (c) to prepare a compound of fo~nula I in which ~ is -C~2-- ~ --~2- / a compound of formula VI:
R-CH2 ~ -X3 VI
in which X3 is CH2E or O~ and R i~ as defined in Claim 1, or a reactive derivative of this compound, is reacted with a coMpound of fo~nula VII:
,, 2 1~
Rl X~ ~ VII
in which X4 is OH (if X3 is CH2E) or CH2E (if X3 is OH) and R1 and R2 are as defined in Claim 1, or with a reactive derivative of thi~ compound, or in that a compound of formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent, and/or in that one or more radicals R1, R2, R3, R~, R5 and/or R6 in a compound of formula I are converted to one o~ more other radicals R , R , R , R , R and/or R , and~or a ba~e or acid of formula I i3 con~erted to one of itR
sal~s.
Above and below, unle~ expressly indicated otherwi~e, the radicals or parame~ers R, Rl to Rl3, X~ A, Ar~ Hal, E, ~ 2~ X3 and X4 are as defined in formulae I to VII.
In the above formulae, A hax 1-6, preferably 1, 2, 3 or 4 C atom~. A is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ~ec-butyl or tert-butyl, or el~e pentyl, 1 ~ 2- or 3 methylbutyl, 1,1-, ~ or 2,2-dLmethylpropyl, l-ethylpropyl, hexyl, 1-, 2-, 3 or 4-methylpentyl, 1,1~, 1,2-, 1,3-, ~,2~, 2,3-or 3,3-dimethylbutyl, 1~ or 2-ethylbutyl, l-ethyl-1-25 methylpropyl, l ethyl-2 methylpropyl or 1,1,2 or 1,2,2-trLm~thylpropyl.
Ar i~ preferably unsubstituted phenyl, or else preferably o-, m- or p-tolyl, o , m- or p-ethylphenyl, o-, m- or p-i~opropylphenyl, o-, m- or p-me~ho~yphenyl, 30 o-, m- or p-etho~yphenyl, o-, m- or p-i~opropoxyphenyl, o , m- or p-trifluoromethylphenyl, o-, m or p-fluoro-phenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl or o-, m- or p~nitrophenyl.
- 7 -- 20~
Hal is preferably F, Cl or Br, or else I.
Alkenyl has 2-6, preferably 2, 3 or 4 C a~o~s and is preferably vinyl, allyl, prop-l-en-l-yl, prop-1-en-2-yl, but~l-, -2- or -3-en-1-yl or but-l~, 2- or -3-en-2-yl.
Alkynyl has 2 6, preferably 2, 3 or 4 C atoms and is pr~ferably ethynyl, prop-l- or -3-yn-1-yl or but-1-, -2- or ~3-yn-1-yl.
In Ar-alkyl the ~alkyl'~ moiety has 1-6, pre-ferably 1, 2 or 3 C atom3. Ar-alkyl is preferably benzyl, 1- or 2-phenylethyl or 1-, 2- or 3 phenylpropyl~
or else preferably o-, m- or p-methylbenzyl, o, m- or p-methoxybenzyl, o-, m- or p-trifluoxomethylbenzyl, o-, m-or p-fluorobenzyl, o-, m- or p-chlorobenzyl, o-, m- or p-bromobenzyl or o-, m or p-nitrobenzyl.
~ 'A substituted by F" is preferably CH2F, CHY2, CF3, CH~-CF3, CF2-CF3, CH2-CH~-CF3, CH2-~2-CF3~ C3F7~ t~F3)2CH
or iso-C3F7.
Cycloalkyl has 3-8, preferably 3, 4, 5 or 6 C
~0 atom~ and i~ pxeferably cyclopropyl, cyclobutyl, cyclo-pentyl or cyclohexyl.
The radicals Rl, R4 and R5 are preferably H in each case, or else preferably A in each ca~e.
The radical R3 is preferably H, CH20R9 (especially CH20A such as methoxymethyl, ethoxymethyl! propoxymethyl, isopropoxymethyl, buto~ymethyl, i~obutoxymethyl, pentoxy-methyl or hexyloxymethyl; or CH20-alkyl-Ar such as ben-zyloxymethyl), CH2RlRll (especially CH2~HRll, in particular CH2NHA such as methyl~minomethyl, ethyl~minomethyl, propylaminomethyl, isopropylaminomethyl, butylamino-methyl, isobutylaminomethyl, pentylaminomethyl or hexyl-aminomethyl; CH2NH-alkyl-Ar such as benzylaminomethyl; or CH2NA-CO-NHAr such as N-methyl-N'-phenylureidomethyl, N-ethyl-N'-phenylureidomethyl, N-propyl-N'-phenylureido-methyl, N-isopropyl-N'-phenylureidomethyl, N-butyl-N'-phenylureidomethyl, N-isobutyl-N'-phenylureidomethyl t N-pentyl-N'-phenylureidome~hyl or N-hexyl-N'-phenyl-ureidomethyl) or tetrazol-5-yl. R3 is also preferably - 8 - 2~P~
COO~ (~specialIy methoxycarbonyl or ethoxycarbonyl), CHO, CN, CH2R~ (especially A such as methyl or ethyl) or CONRlQRll such as CONH2.
very particularly preferred radicals R3 are H or tetrazol-5-yl, or else butoxym~thyl, benzyloxymethyl, butylaminomethyl, benzyla~inomethyl and N-butyl-N~-phenylureidomethyl.
The radical R3is preferably linear and is prefer-ably A or alkenyl having 3-6 C atoms in each case, especially butyl, or else propyl, pentyl, hexyl, allyl or prop-1-enyl, or else but-l-enyl, pent-1-enyl, hex-l-enyl, prop-l-ynyl, but-l-ynyl, pent-1-ynyl or hex-l-ynyl.
The radical R7 is preferably A, especially methyl (~ or ethyl, or CF3.
The radi~al R8 i8 preferably ~, F, Cl, A, CN, COOH, COOA or tetrazol-5-yl.
The radical R9 is preferably H, A (especially having 3-5 C atoms) or benzyl.
The radical Rl is preferably H, A or benzyl.
The radical Rl iS preferably ~, ~ (especially having 1-5 C atoms), A polysubstituted by F, benzyl, CO-A, CO-Ar, CO-CH2C6H5, COOA, COOAr, COOCH2CsHs, CONH2, CONHA, CONH-cycloalkyll CONA2 or CONHAr.
The radical ~ is preferably absent or is pre-ferably -NH-CO- or -CO-NH-~
The compound3 of formula I can possess one or more chiral cen~res and can ther~fore exist in different forms (optically active or optically inactive). Formula I includes all the~e forms.
Accordingly, the invention relates especially to those compounds ~f formula I in which at least one of said radicals has one of the preferred meanings indicated above. Some preferred yroups of compounds can be expressed by the following partial formulae Ia to Ig, which correspond to formula I and in which the radicals not described more precisely are as defined in formula I, except that in Ia: R3 is H;
2 0 7 ~
in Ib: R-'is COOH~ COOA or CONRlR~l;
in Ic: R3is CHO or CN;
in Id~ R is CH2R~;
in Ie: R3is CH20R8;
5 in If R3is NRl~Rl~ or C~ NRlRll; and in Ig: R is tetrazol-5-yl.
Particularly preferred compounds are those of formulae Ih and Iah to Igh, which correspond to formulae I and Ia to Ig except that in addition X is absent.
Other preferred compounds are those of formulae Ii and Iai to Igi, which correspond to formulae I and Ia to Ig excep~ that in addition X is -CO-.
Other preferred compounds are those of formulae I~ and Iaj to Igj, which correspond to formulae I and Ia to Ig except that in addition X is -O-.
Other preferred compounds are those of formulae Ik and Iak to Igk, which correspond to formulae I and Ia to Ig except that in addition X is -NH-CO-.
Other preferred compounds are those of formulae Il and Ial to Igl, which correspond ~o formulae I and Ia to Ig except ~ha~ in addition X is -CO-NH-.
Other preferred compound~ are those of formulae Im and Iam to Igm, which correspond to for~ulae I and Ia to Ig except that in addition X i~ -CH2-O-.
Other preferred compounds are those of formulae In and Ian to Ign, ~hich correspond to formul~e I and Ia to Ig except that in addition X i~ -O-CH2-.
Particularly preferred compounds are those of formulae I, Ia to In and Iah to Ign in which in addi~ion R1 is H and/or R~ and/or R5 are H or A and~or R6 is A
(especially propyll butyl or pentyl).
Among these, preferred compounds are those in which R2 i~ COOH, COOCH3, COOC2Hs, C~ or tetrazol-S-yl.
A v~ry particularly preferred group of compounds i8 that of formula I in which Rl is H, R2 i8 COOH, COOA, CN or tetra~ol-S-yl, 2~7~
1 o --R3 is H~ C~20~, CH20CH2~6H5, CH2N~A, CH~NHCH2C6H5, CH2.~ACONHC6H5 or tetrazol-S-yl~
R' and R3 are H or A in each case, 5 R~ is A and X is absen~.
A small selected group of preferred compounds is that of formula I in which R, R
10 and R5 are H in each case, R2 is CN or tetrazol-5-yl, R3 is H, CH20-alkyl having 3-5 C atoms in the alkyl group, or tetrazol-5-yl, R6 is al~yl having 3-5 ~ atoms and 15 X is abs~nt.
The compound~ of formula I and al~o the starting material~ for their prepara~ion are moreov~r prepared by methods known per se~ such as those described in ~he literature ~or ~xampl~ in the ~tandard works like Houben-Weyl, ~ethoden der organischen Chemie (Methods of Organic Chemi3try~, Georg-Thieme-V~rlag~ Stuttgart, but especially US patent 4 880 804), under reaction condi-tions which are known and suitable for ~aid reaction~, it also bein~ possibl~ to make use of variants known per se~
which are not ~entioned in greater detail here.
If desired, the starting materials can al~o be formed in situ, ~o that they are not isolated from thc reaction mixture but immediately reacted further to give the compo~lnds of formula I.
The compound~ of formula I can preferably be obtained by reacting compounds of formula II with com-pounds of fonmula III. Particularly the biphenyl deriva~
~ives of formula I (in which X i~ absent~ are readily obtainable in this way.
1 1 2077~ 3 In the compound~ of formula II~ E is preferably Cl, Br, I or an OH group which has been ~unctionally modified to acquire reac~ivity~ such a~ al ~lsulfonyloxy having 1-6 C atoms (preferably methylsulfonyloxy) or S arylsulfonylo~y having 6-10 C atoms (preferably phenyl-or p-tolyl-sulfonyloxy).
The reaction of II with III is conveniently carried out by first converting III to a salt by treat-ment with a base, f or example with an alkali metal alcoholate such as C~30Na in an alcohol ~uch as CH30H, or with NaH or pota~sium tert-butylate in dimethylformamide (DMF), and then reacting said salt with II in an inert solvent, for example an amide such as DMF or dimethyl acetamide, or a sulfoxide such as dLmethyl sulfoxide (DMSO), conveniently at temperature~ of between -20 and 00 D ~ pref~ra~ly of between 10 and 30.
Acid amides of formula I (X = -~H CO- or -CO-NH-) can also be obtained by reacting compound~ of formula IV
50r reactive d~ri~ative~ thereof) wi~h oompounds of formula V (or reactive derivative~ thereof). Suitable reactive derivative~ cf the carboxylic acid~ of formulae IV and V ~Xl or X~ = COOH~ are advanta~eously the corresponding chloride~, bromides or anhydrides. Th~
reaction is conveni~ntly ~Arried out in the presence of ~5 an inert ~olvent, for example a halogenated hydrocarbon such as methylene chloride, chloroform, tri~hloroethene or 1,2-dichloroe~hane, or an ether such as tetrahydro-furan (THF) or dioxane~ at temperatures of between O and 150, preferably of between 20 and 80. If acid halides are reacted, it is recommended to add a base, for example a tertiary amine such a~ triethylamine, pyridine or 4-dLmethylaminopyridine.
Ethers of formula I (X = -CH2-O~ or -O-C~2-) can be obtained by reacting compounds of formulae VI and VII
(or reactive derivatives thereof). Examples of suitable reactive derivatives of the phenol3 VI and VII (X3 or X4 = OH) are the corresponding alkali metal (for example Na, ~ phenolate~l which can al~o be formed in situ from the phenol and a has2 ~for example potassium carbonate). ~h~
reaction is conveniently carried out in the presence of an inert solvent, for example an amide such as DMF or a sulfoxide such as DMSO, at temperatures of between 0 and l50~, preferably of between 20 and l00.
Some of the starting materials of formulae II, III, IY, V, VI and VII are known. If they are not known, they can be prepared by known methods analogously to known substances. Compounds of formula II are extensive-10 ly known (compare, for example, EP-A2-400974~. Compounds of formula III can be obtained for example by reacting ketones of the formula R6-Co-CH2-R5 (preferably R~-CO-CH3) with esters of the formula R4-CooA (preferably HCOOA, especially HCOOC2H5) to give dicarbonyl compounds of the formula R6_co-c~5=cR4-oH (preferably R6-CO-CH=CH-O~;
"enolone form~') and then conden~ing these with aceta~ide3 of the formula R3-CH2 CON~2, especially cyanoaceta~ide.
It is thus possible in particular to obtain 3-cyano-4-R4-S-Rs-6-R6-l t 2-dihydro-2-oxopyridines (for~ula XII, ~0 R3 = CN, R4 = R5 = H), for example 6-butyl-3 cyano-l,2-dihydro-2-oxopy~idine ("IIIb"). The f~llowing are examples of compounds which can be ob~ained from these 3-cyano compounds: by hydrolysis (for example with hydro-chloric acid), the carboxylic acids (III, R3 = COOH); from these, by esterification ( for example with an alcohol A-OH in the presence of a strong acid), the esters (III, R3 = COOA~; by decarboxylation, the l,2-dihydxo 2-oxopyridines unsubstituted in the 3-position lIII, R3 = H); by reduction, the 3-hydroxymethyl compounds (III, R3 = CH20H) or the 3-aminomethyl compound~ tIII, R3 = CH2NH2l; and by oxidation of the latter, for example with ~nO2, the aldehydes (III, R3 = CHO), which can al~o be prepared from the nitriles by reaction with diiso-butylaluminium hydride. Partial hydrolysis of the 35 nitriles (III, R3 = C~; for example with 90~ H2SO4;
compare US-Al-4 137 233) gives the carboxamides (III, R3 = CONH2), which can be degraded with NaOH/sr2 to the 3-amino compounds (III, R3 = NH2) (compare -- 13 - ~7 US-A-l~ 13~ 233).
To convert a radical R3 in ~tarting materials of formula III, it i5 al50 possible to block the 2-oxo group as an interm~diate step. Thus, for e~ample, nitriles (III, R3 = CN) can be converted to the corresponding 2 ben~yloxy-3-cyano-4-R4-5-R~-6-R6-pyridines with benzyl chloride/AgzO in boiling toluene; the corresponding 3-carboxylic acids can be ob~ained from these ~y boiling with ethanolic ROH and the corresponding 3-hydroxymethyl compounds can be obtained by reducing said acids.
Alkylation, for example with iodides of the formula A-I, gives the corresponding 2-benzyloxy-3-alkoxymethyl-4-R4-5-R5-6-Rs-pyridines, which can be hydrogenolysed to compounds of formula III (R3 = A-O-CH2~
A compound of formula I can also be liberated from one of its functional derivatives by treatment with a solvolysing Ifor example hydrolysing) or hydrogeno-ly~ing agent.
It is thus possible, using one of the indicated methods, to prepare a compound which has formula I but in which the ~etragol-5-yl group is replaced with a tetrazol-S-yl group functionally modified in the l-position (pro~ected by a protecting group). Examples of suitable prote~ting groups are: triphenyl~ethyl, which can be cleaved with HCl in an inert solvent or solvent mixture~ for example ether/methylene chloride/methanol;
2-cyanoethyl, which can be cleaved with NaOH in wa~er/THF; and p nitrobenzyl, which can be cleaved with ~2/Raney nickel in ethanol (compare EP-A2-0 291 969).
It is also possible to conver~ one compound of formula I to another compound of formula I by converting one or more of the radicals R1, R2, R3, R4, R5 and/or R6 to other radical~ Rl, R2, R3, R4, R5 and/or R6, for example by reducing nitro group~ to amino groups (for example by hydrogenation on Raney nickel in an inert solvent such as methanol or ethanol), and/or functionally modifying free mino and~or hydroxyl groups, and/or liberating functionally modified amino and/or hydroxyl groups by -- 1 A _ 2 0 7 7 ~1 1 r l solvolysis or hydro~enolysis~ and~or replacing halogen atoms with OA or CN groups (for example by reaction with alkali metal alcoholates or with copper(I) cyanide~, and/or hyd.rolysing ni~rile groups to CONH2 or COOH groups, or converting nitrile groups to tetrazolyl groups with hydrazoic acid deriva~ives, andtor reducinq CHO groups to CH20H groups (for example with NaBH4), or converting CHO
groups to aminomethyl, A-NH-CH2 or Ar-alkyl-NH-CH2 group~
( f or examp~ e ~ith ammonia or prLmary amines in the presence of a reducing agent such as NaCNBH3), and/or degrading CONH2 groups to NH2 groups (for example with Br2/ aqueous NaOH solution).
Thus, for example, free hydroxyl and~or amino qroups can be acylated in a conventional manner with an acid chloride or anhydride, or alkylated with an alkyl or aralkyl chloride or bromide, conveniently in an inert solvent such as methylene chloride or THF, and/or in the presence of a base such as triethylamine or pyridine, at temperature~ of between -60 and +30. The conversion of prLmary amino groups to secondary or tertiary amino group~ is al~o effected by reaction with appropriate aldehydes or ketones in the presence of a reducing agent.
If desired, a functionally modified amino and~or hydroxyl group in a compound o~ formula I can be liberated by solvolysis or hydrogenolysis using conven-tional methods. Thus, for example, a compound of formula I containing an NHCoR7 ~ NHCOOA or AOOC group can be converted ~o the corresponding compound of formula I
containing an NH2 or H~OC group instead. AOOC groups can be ~aponified for example with NaOH or KOH in water, water/THF or water/dioxane at temperature~ of between O
and 100 9 .
The reaction of nitriles of formula I (R2 and/or R3 = CN) with hydrazoic acid derivative~ gives tetrazoles of formula I ~R2 and/or R3 = tetrazol-5-yl). It iæ
pref~rable to use trialkyltin azides such as trLmethyltin azide, in an inert ~olvent, for example sn aromatic hydrocarbon such as toluene, at temperatures of between ~r ~77~
20 and 15Q~, preferably of between 80 and 140, or sodi~m a~ide in N-methylpyrrolidone at temperatures of between about 100 and 200.
A base of formula I can be converted with an acid to the corresponding acid addition salt. Possible acids for this reaction are especially those which yield physiologically acceptable salts. Thus it is pos~ible to use inorganic acids, for exampl~ sulfuric a~id, nitric acid, hydrohalic acids such as hydrochloric acid or lQ hydrobromic acid, phosphoric acid~ such as orthophos-phoric acid, and sulfamic acid, as well as organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pi~alic acid, diethylacetic acid, mal~nic acid, succinic acid, pLmelic acid, fuma~ic a~id, maleic acid, lactic acid, tartaric acid, malic acid, ~itric acid, gluconi~ acid, ascorbic acid, nicotinic acid~
isonicotinic acid, meth~ne- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzene~ulfonic acid, p-toluene~ulfonic acid, naphtha-lene-monosulf OniG and -di~ulfonic acid~ and lauryl-sulfuric acid. Salt~ with phy~iologically unacceptable acids, for example picrate~, can be used for isolating and/or purifying the compound~ of formula I.
On the other hand, compounds of formula I con-taining COOH or tetrazolyl groups can be converted with bases (for sxample sodium or pota~sium hydroxide or carbonatej to the corresponding metal saltQ, especially alkali metal or alkaline earth metal salts, or to the corresponding ammonium salts. The potassium sal~ of the tetrazolyl derivative~ are particularly pref erred .
The novel compounds of formula I and thair phy~iologically acceptable salt~ can be used for the 35 manufacture of pharmaceutical preparations by incorpora-tion into a ~uitable dosage form together with at least one excipient or ad~unct and, if de~ired, together with one or more other active inyredients. The re~ulting 2~77`~
~ lh -formulations can be used as drugs in human or veterinary medicinP. Possible excipients are organic or inorganic substances which are suitable for enteral ~for example oral or rectal) or parenteral administration or for adminis~ration in the form of an inhalation spray, and which do not react with the novel compounds, for example water, vegetable oil~, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycer-ides, gelatin, ~oya lecithin, carbohydrates such as lactoRe or starch, magnesiu~ stearate, talc and cellulose. Tablets, coated tablets, capsules, syrups, juices or drops, in particular, are used for oral admini-stration; film-coated tablet~ and capsule~ with coatings or shells resistant to gastric ~uice are of special interest. Suppositorie5 are used for rectal admini-~tration and solution~, preferably oily or aqueou~
solutions, as well as ~uspensions, emulsinns or Lmplants, are u~ed for parenteral administration. For admini-stration as inhalation spray~, it i8 possible to us~
sprayq containing tha active ingredient either di ~olved or ~u~pended in a propollant mixture (f~r e~a~ple chloro_ fluorocarbons). It is con~enient here to use the acti~e ingredient in micronised form, it being possible for one or more additio~al physioloqically compatible solvents, 25 for example ethanol, to be present. Inhalation solutions can be admini~ered with the aid of conventional inhalers. The novel compou~d~ can also be lyophilised ~nd the resulting lyophili~ate~ used for example for the manufacture of in~ectable preparation~. The indicated form~lations can be ~t~rilised ~nd~or can contain ad~unct3 3uch as preservatives, stabili~ers and/or wetting agents, emulsifier~, salt~ for influencing the osmotic pre~ure, buffer ~ubstance and colorant~ andtor flavouring~. If desired, they can alRo contain one or more other acti~e ingredients, for example one or more vitamins, diuretic~ or antiphlogistics.
The sub~tances according to the invention are normally admini~ered analogously to other known, commercially ~vailable preparations, but in par~icular analogously to the compounds de~cribed in US paten~
4 830 804, preferably in doses of between about 1 m~ and 1 g, especially of between 50 and 500 mg per dosage unit.
The daily dose is preferably between about 0.1 and 50 mg~kg, especially between 1 and 10 ~g/kg of body weight. However, the particular dose for each individual patient depends on a very wide variety of factors, for example on the efficacy of the particular compound used, age, body weight, general state of he21th, sex, diet, time and method of administration, rate of excretion, drug combination and severity of the particular disease to which the therapy is applied. Oral administration is preferred.
Above and below, all temperatures are qiven in ac. In the examples which f~llow, "con~entional w~rki~g-up~ means water is added if necessary, the p~ is ad~usted to between 2 and 10 if necessary; depending on the constitution of the end product, extraction is c~rried out with ethyl acetate or methylene chloride and the organic phas~ i separated off, dried over sodium sulfate, evaporated and purified by chromatography on silica gel and/or by crystallisation.
M+ = molecular peak in the mass spectrum. Rf values by thin layer chxoma~ography on silica gel with methylene chloride/methanol (99:1 unless indicated otherwise).
Ex~mple 1 1.12 g of potas~ium t2rt-butylate are added to a ~olution of 1.5 g of 6~butyl-1,2-dihydro-2-oxopyridine ["IIIa"; m.p. 6g; ob~ainable by condensation of hexan-2-one with ethyl formate in toluene, in the presence of NaOCH3, to give 1-hydroxyhept-1-en-3-one, condensation with cyanoacetamide in water, in the presence of piperi-dine and acetic acid, at 30, to give 6-butyl-3-cyano-1,2-dihydro-2-oxopyridine ("IIIb ; m.p. 110), hydrolysis with 37% hydrochloric acid (boiling for 5 hours) to give 6-butyl-1,2-dihydro~2-oxopyridine-3-chrboxylicacid(m.p.
~077~
149~) and decarboxylation at 180-200] in 25 ml of D~E.
The mixture is sti~red for lO minute~, a solution of 2.72 g of 4'-bromomethyl-2-cyanobiphenyl ("IIa") in 15 ml of DMF is added dropwise over 30 ~inut~s and the r~sult-5 ing mixture i~ stirred for 16 hours at 20. It isevaporat~d, worked up in a conventional manner (pH 7 ethyl acetate~ and purified by chromatography ~silica gel; ~ethylene chloride/ methanol 98:2) to give 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridins;
Rf 0.4; ~M~H)+ 343. 6-Butyl-2-(2'-cyanobiphenyl-4-yl-methoxy)pyridine is obtained as a by-product.
The following are obtained analogously from IIIa2 with 4-bromomsthyl~2'-methoxycarbonylbenzanilide (m.p.
151; obtainable from 4-methyl-2'-methoxycarbonylbenz-anilide and N-bromosuccinimide in methylene chloride).
The daily dose is preferably between about 0.1 and 50 mg~kg, especially between 1 and 10 ~g/kg of body weight. However, the particular dose for each individual patient depends on a very wide variety of factors, for example on the efficacy of the particular compound used, age, body weight, general state of he21th, sex, diet, time and method of administration, rate of excretion, drug combination and severity of the particular disease to which the therapy is applied. Oral administration is preferred.
Above and below, all temperatures are qiven in ac. In the examples which f~llow, "con~entional w~rki~g-up~ means water is added if necessary, the p~ is ad~usted to between 2 and 10 if necessary; depending on the constitution of the end product, extraction is c~rried out with ethyl acetate or methylene chloride and the organic phas~ i separated off, dried over sodium sulfate, evaporated and purified by chromatography on silica gel and/or by crystallisation.
M+ = molecular peak in the mass spectrum. Rf values by thin layer chxoma~ography on silica gel with methylene chloride/methanol (99:1 unless indicated otherwise).
Ex~mple 1 1.12 g of potas~ium t2rt-butylate are added to a ~olution of 1.5 g of 6~butyl-1,2-dihydro-2-oxopyridine ["IIIa"; m.p. 6g; ob~ainable by condensation of hexan-2-one with ethyl formate in toluene, in the presence of NaOCH3, to give 1-hydroxyhept-1-en-3-one, condensation with cyanoacetamide in water, in the presence of piperi-dine and acetic acid, at 30, to give 6-butyl-3-cyano-1,2-dihydro-2-oxopyridine ("IIIb ; m.p. 110), hydrolysis with 37% hydrochloric acid (boiling for 5 hours) to give 6-butyl-1,2-dihydro~2-oxopyridine-3-chrboxylicacid(m.p.
~077~
149~) and decarboxylation at 180-200] in 25 ml of D~E.
The mixture is sti~red for lO minute~, a solution of 2.72 g of 4'-bromomethyl-2-cyanobiphenyl ("IIa") in 15 ml of DMF is added dropwise over 30 ~inut~s and the r~sult-5 ing mixture i~ stirred for 16 hours at 20. It isevaporat~d, worked up in a conventional manner (pH 7 ethyl acetate~ and purified by chromatography ~silica gel; ~ethylene chloride/ methanol 98:2) to give 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridins;
Rf 0.4; ~M~H)+ 343. 6-Butyl-2-(2'-cyanobiphenyl-4-yl-methoxy)pyridine is obtained as a by-product.
The following are obtained analogously from IIIa2 with 4-bromomsthyl~2'-methoxycarbonylbenzanilide (m.p.
151; obtainable from 4-methyl-2'-methoxycarbonylbenz-anilide and N-bromosuccinimide in methylene chloride).
6-butyl-1-[4-(2-methoxycarbonylanilinocarbonyl)-benzyl]-1,2-dihydro-2-oxopyridine;
with 4-bromomethyl-2'-ni~robiphenyl:
6-butyl-1-(2'-nitrobiphenyl-4-ylmethyl)-1,2~dihydro-2-oxopyridine;
with 4-bromomethyl~2'-me~hoxycarbonylben~ophenone:
6-butyl-1-[4-(2~methoxycarbonyl~enzoyl)benzyl]-1,2-dihydro-2-oxop~ridine;
with 4-(2-cyanoben~amido)benzyl bromide:
6-butyl-1-[4-(2 cyanobenzamido)benzylJ-1,2-dihydro-2-oxopyridine with 4-~2-cyanoanilinocarbonyl)benzyl bromide:
6-butyl l-[4-(2-cyanoanilinocarbonyl)benzyl3-1,2-dihydro-2-oxopyridine.
Example 2 The following are obtained from IIa analogously to Example l:
with methyl 6-butyl-1,2-dihydro-2-oxopyridine-3-car-boxylate [m.p. 126; obtainable by e~terification of the 2~77~ ~ t;~J
carboxylic acid (m.p. 149; se~ Example 1)]:
methyl 6-butyl~ 2~-cyanobiph~nyl-4~ylmethyl)-lr -dihydro-2-oxopyridine-3-carboxylate,m.p. 142, with 6-butyl-3-carbamoyl-1,2-dihydro-~-oxopyridine (m.p.
205; obtainable from IIIb and 90% H25O4):
6-butyl-3-carbamoyl-1-(2'-cyanobiphen~1-4-ylmethyl)-1~2-dihydIo-2-oxopyridine;
with 6-butyl-1,2-dihydro-2-oxo 3-formylpyridine (m.p.
118; obtainable from IIIb with dii~obutylaluminium hydride in toluene at -65):
6-butyl-1-~2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-formylpyTidine;
with IIIb:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-~-oxo-3-cy~nopyridine; Rf 0.25;
with 6-butyl-1,2-dihydro-2-oxo-3-nitropyridine:
6-butyl-1-(2'-cyanobiphenyl~4-ylmethyl)-1,2-dihydro-2-oxo-3-nitropyridine;
with 6-butyl-1,2 dihydro-2-oxo-3-dimethylaminocarbonyl-pyridine:
6-butyl~ cyanobiphenyl 4 ylm~thyl~-1,2-dihydro~
2-oxo-3-dLmethylaminocarbQnylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-pyrrolidinopyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-pyrrolidinopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-piperidinopyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro 2-oxo-3-piperidinopyridine;
with 6 butyl-1,2~dihydro-2-oxo-3-succinimidopyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2~dihydro-2-oxo-3-~uccinimidopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-phthalimidopyridine-6 -butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-phthalLmidopyridine;
35 with 6-butyl-1,2-dihydro 2-oxo-3-acetamidopyridine:
6-butyl-1-(2'-cyanobiphe~yl-4-ylmethyl)-1, 2-dihydro-2-oxo-3-acetamidopyridine;
with 4-bromomethyl-2'-ni~robiphenyl:
6-butyl-1-(2'-nitrobiphenyl-4-ylmethyl)-1,2~dihydro-2-oxopyridine;
with 4-bromomethyl~2'-me~hoxycarbonylben~ophenone:
6-butyl-1-[4-(2~methoxycarbonyl~enzoyl)benzyl]-1,2-dihydro-2-oxop~ridine;
with 4-(2-cyanoben~amido)benzyl bromide:
6-butyl-1-[4-(2 cyanobenzamido)benzylJ-1,2-dihydro-2-oxopyridine with 4-~2-cyanoanilinocarbonyl)benzyl bromide:
6-butyl l-[4-(2-cyanoanilinocarbonyl)benzyl3-1,2-dihydro-2-oxopyridine.
Example 2 The following are obtained from IIa analogously to Example l:
with methyl 6-butyl-1,2-dihydro-2-oxopyridine-3-car-boxylate [m.p. 126; obtainable by e~terification of the 2~77~ ~ t;~J
carboxylic acid (m.p. 149; se~ Example 1)]:
methyl 6-butyl~ 2~-cyanobiph~nyl-4~ylmethyl)-lr -dihydro-2-oxopyridine-3-carboxylate,m.p. 142, with 6-butyl-3-carbamoyl-1,2-dihydro-~-oxopyridine (m.p.
205; obtainable from IIIb and 90% H25O4):
6-butyl-3-carbamoyl-1-(2'-cyanobiphen~1-4-ylmethyl)-1~2-dihydIo-2-oxopyridine;
with 6-butyl-1,2-dihydro-2-oxo 3-formylpyridine (m.p.
118; obtainable from IIIb with dii~obutylaluminium hydride in toluene at -65):
6-butyl-1-~2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-formylpyTidine;
with IIIb:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-~-oxo-3-cy~nopyridine; Rf 0.25;
with 6-butyl-1,2-dihydro-2-oxo-3-nitropyridine:
6-butyl-1-(2'-cyanobiphenyl~4-ylmethyl)-1,2-dihydro-2-oxo-3-nitropyridine;
with 6-butyl-1,2 dihydro-2-oxo-3-dimethylaminocarbonyl-pyridine:
6-butyl~ cyanobiphenyl 4 ylm~thyl~-1,2-dihydro~
2-oxo-3-dLmethylaminocarbQnylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-pyrrolidinopyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-pyrrolidinopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-piperidinopyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro 2-oxo-3-piperidinopyridine;
with 6 butyl-1,2~dihydro-2-oxo-3-succinimidopyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2~dihydro-2-oxo-3-~uccinimidopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-phthalimidopyridine-6 -butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-phthalLmidopyridine;
35 with 6-butyl-1,2-dihydro 2-oxo-3-acetamidopyridine:
6-butyl-1-(2'-cyanobiphe~yl-4-ylmethyl)-1, 2-dihydro-2-oxo-3-acetamidopyridine;
7 '~
with 6-butyl-1~2-dihydro-2-oxo-3-trimethylacetamido-pyridine:
6-buty~ 2~-cyano~iphenyl-4-ylme~hy~ 2 dihydro-2-oxo-3-trLmethylacetamidopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-benzamidopyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-ben~amidopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-tert-butoxycarbonyl-aminopyridlne:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl~-1,2-dihydro-2-oxo-3-tert-butoxycarbonylaminopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-N'-butylureidopyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-N'-butylureidopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-N'-phenylureidopyridine, 6-butyl 1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-N'-phenylureidopyridine;
with 6-butyl~1,2 dihy~r~ 2 oxo-3-N'-benzylureidopyridine:
6-butyl~ 2'-cyanobiph~nyl-4-ylmethyl)~1,2~dihy~ro ~-oxo-3-~'-ben~ylureidopyridine;
with 6-butyl~1,2-dihydro-2-oxo-3 N-methylbenzamidopyTi-dine:
6-butyl-1-(2'-cyanobiphenyl-4~ylmethyl)-1,2-dihydro-2-oxo-3~N methylbenzamidopyridine;
with 6-butyl-112-dihydro-2~oxo~3-methylpyridine ~obtain-able by hydrogenolysi~ of ~-ac~togymethyl-2-benzyl-oxy-~-butylpyridine on Pd/C in ethanol at 20 and 1 bar~:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl~-1,2-dihydro-~-oxo-3-methylpyridine; m.p. 126~; Rf 0.4;
with 6-butyl-1~2-dihydro-2-oxo-3-fluoromethylpyridine:
6-butyl~l (2'-cyanobiphenyl-4-ylmethyl)-1,~-dihydro-2-oxo-3-fluoromethylpyxidine;
with 6-butyl-1,2-dihydro-2-oxo-3-chlorome~hylpyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-chloromethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-cyanomethylpyridine:
2 0 ~
' 6-bu~yl~ cyanobiphenyl-4-ylmethyl)-l,2-dihydro-2-oxo-3-cyanomethylpyridine;
with ethyl 6-b~yl-1,?-dihydro-2-oxopyridine-3-acetate:
ethyl 6-~u~yl-1-(2'-cyanobiphenyl-4-ylmethyl~-1,2-S dihydro-2-oxopyridine-3-acetate;
with 6-butyl-1,2-dihydro-2-oxo-3-methoxymethylpyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-methoxym~thylpyridine;
with 6-butyl-l,2-dihydro-2-oxo-3-isopropoxymethylpyri-dine:
6-butyl-1-(2'-cyanobiphenyl-4-yLmethyl)-1,2-dihydro-2-oxo-3-isopr~poxymethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-butoxymethylpyridine ~oil; obtainable by reaction of IIIb with benzyl chloride in the presence of Ag20 in toluene (boiling for 24 hours~ to give 2-benzyloxy-6-butyl-3-cyano-pyridine ~oil), hydrolysis with aqueous-ethanolic KOH (boiling fo~ 48 hours~ to give 2-benzyloxy-6-butylnicotinic acid, reduction with LiAlH4 in THF to gi~e 2-benzyloxy-6-butyl-3-hydIoxymethylpyridine~
alXylation with butyl iodide in THF in the presence of NaH to give 2-benzyloxy-6-butyl-3-butoxymethyl-pyridine, and hydrogenolysis on 5~ Pd/C in methanol]~ -6-butyl-1-~2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-butox~methylpyridine; Rf 0.2;
with 6-butyl-1,2-dih~dro 2-oxo-3-benzyloxymethylpyridine:
6-butyl-1-(2~ cyanobiphenyl-4-yLmethy~ 2-dihydro 2-oxo-3-benzyloxymethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-acetamidomethylpyridine:
6-butyl-1-(2'-c,yanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-acetamidomethylpyridine,m.p. 150;
with 6-butyl-1,2-dihydro~2-oxo-3-butyramidomethylpyri-dine:
6-butyl-1-(2'~cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-butyramidomethylpyridine;
with 5-butyl-1,2-dihydro-2-o~o-3-phenylacetamidomethyl-pyridine:
20~7~ ~ ~
6-~utyl~ 2~-~ydnQbiphenyl-4-ylmethyl)-1,2-dihydLo-2-oxo-3-phenyl~cetamidomethylpyridine;
wi~h 6-butyl-1,2-dihydro-2-oxo-3-tert-butoxycarbonyl-aminomethylpyridine:
6-b~tyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2 dihydro-2-oxo-3-tert-butoxycarbonylaminomethyl pyridine,~.p.105~;
with 6-butyl-1,2-dihydro-2-oxo-3-phenoxycarbonylamino-methylpyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-phenoxyca~bonylaminomethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-benzyloxycarbonyl,~mino-methylpyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl~-1,2-dihydro-2-oxo-3-benzyloxycarbonylaminomethylpyridine oil, RfO.58 (ethylacetate~hexane 1:1);
with 6-butyl-1,2~dihydro-2-oxo-3-ureidomethylpyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylm~thyl) 1,2~dihydro-2-oxo-3-ureidomethylpyridine, m p.166, with 6-butyl-1,2-dihydro-2-oxo-3-~N'-butylureidomethyl)-pyridine:
6-butyl-1-(2'-cyanobiphenyl-4-yL~ethyl)-1,2-dihydro-2-oxo-3-(N'-butylureidomethyl)pyridine! m.p. 61, with 6-butyl-1,2-dihydro-~-oxo-3-(N~-cyclohexylureido-methyl~pyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl) 1,~-dihydro-2-oxo-3-(N'-cyclohexylurcidomethyl)pyridine,m.p.g8;
with 6-butyl-1,2-dihydro-2-oxo-3-(N'-phenylureidomethyl)-pyridine:
6-butyl-1-(2'-cyanobiphenyl-4 ylmethyl ) -1, 2-dihydro-2-oxo-3-(N'-phenylureidomethyl)pyridine,m.p.89-;
with 6-butyl-l~2-dihydro-2-oxo-3-( N ', N '-dimethylureido-methyl)pyridine:
6-butyl~ 2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydxo-2-oxo-3-(N',N'-dimethylureidomethyl)pyridine,m.p.60;
with 6-butyl-1,2-dihydro-2-oxo-3-diethylaminomethyl-pyridine:
6-butyl-1-(2'-cyanobiphenyl-4 ylmethyl)-1,2-dihydro-2-oxo-3-diethylaminome~hylpyridine;
~77~
- ?3 -with 6 butyl-1,2-dihydro-2 oxo-3-diisopropylaminomethyl-pyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylme~hyl)~1,2-dihydro-2-oxo-3-diisopropylaminomethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-pyrrolidinomethylpyri-dine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl) 1,2-dihydro-2-oxo-3-pyrrolidinomethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-piperidinomethylpyri-dine:
6-butyl-1 ~2'-cyanobiphenyl-4-yLmethyl)-1,2-dihydro-2-oxo-3-piperidinomethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-(N-methylacetamido-methyl~pyridine:
5-butyl-1-(2'-cyanobiphenyl-4-yLmethyl)-1,2-dihydro-2-oxo- 3-(N-methylacetamidomethyl)pyridine;
with ~-butyl-1~ 2-dihydro-~-oxo-3-(N-isopropylace~amido-methyl)pyridine:
6 butyl-1~ cyan~biphenyl-4-ylm~thyl)-1 J 2-dihydro 2-oxo-3-~N-i~opropylacatamidomethyl)pyridine with 6-butyl-1,2-dihydro-2-oxo-3-~N-butyl-N'-methyl-ureidomethyl)pyridine:
6-butyl-1-(2.'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-(N-butyl-N'-methylureidomethyl)pyridine;
with 6-butyl 1,2-dihydro-2-oxo-~-(N,N'-dimethylureido-ethyl)pyridine:
6-butyl-1-(2' -cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-(N,N'-dimethylureidomethyl)py~idine;
with 6-butyl-1,2-dihydro-2 oxo-3-(N,N',N'-trimethyl-ureidomethyl)pyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-(N,N',N'-trimethylureidomethyl)pyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-(N-butyl-N'-phenyl ureidomethyl)pyridine:
6-butyl-1-(2'-cyanobiphenyl-4 ylmethyl)-1,2-dihydro-2-oxo-3-(N-butyl N'~phenylureidomethyl)pyridine;
with 6-butyl 1,2 dihydro-2-oxo-3-~N-benzyl-N'-methyl-ureidomethyl~pyridine:
~77'~h 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1~2-dLhydro~
2-QXo- 3-(N-benzyl-N'-methylureidomethyl)pyridine;
with 6-butyl-1,2 dihydro-2-oxo-3-(N-butyl-N-iSobutoxy-carbonylaminomethyl)pyridine:
6-butyl-1-(2~-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-(N-butyl-N-isobutoxycarbonylaminomethyl) pyridine;
with 6-butyl-1,2-dihydro~2-oxo-3-(N-isopropyl-N-benzyl-oxycarbonylaminomethyl)pyridine:
6-butyl-1-(2'-cyanobiphenyl-4-y~methyl)-1, 2-dihydro-2-oxo-3-(N-isopropyl-N-benzyloxycarbonylamino-methyl)pyridine;
with 4-methyl-1l2-dihydro-2-oxopyridine:
4-methyl-1,2-dihydro 2~oxo-1-(2'-cyanobiphenyl-4-ylmethyl)pyridine; Rf 0.1, with 1,2-dihydro-2-oxo-6-phenylpyridine:
1-(2'-cyanobiphenyl-4-ylmethyl) 1,2-dihydro-2-o~o-6-phenylpyridine; Rf 0.~;
with methyl 6 isobu~yl-1,2-dihydro-2-oxopyridine-3-carboxylate (obtainablP analogou~ly to IIIa from 4-methylpantan-2~one via 1-hydroxy-5-methylhexen-1-one, 6-isobutyl-1~2-dihydro-2-oxo-3-cyanopyridine and 6-isobutyl- 1,2-dihydro-2-oxopyridine-3-carboxylic acid):
methyl 1~ cyanobiphenyl-4-ylmethyl)-6-isobutyl-1,2-dihydro-2-oxopyridine-3-carboxyla~e; R 0.5;
with 3-cyano-6-methyl-1/2-dihydro-2-oxo-5-propylpyridine (formed a~ a by product in the prepar~tion of IIIb):
3-cyano~ 2'-cyanobiphenyl 4-methyl)-6-methyl-1,2-dihydro-2-oxo~5-propylpyridine; m.pO 186;
with 6Imethyl-~ 6-ethyl-, Ç-propyl- or 6-pentyl-1,2-dihydro-2-oxopyridine:
1~2'-cyanobiphenyl-4-ylmethyl)-6-methyl 1,2-di-hydro-2-oxopyridine;
1-(2'-cyanobiphenyl-4-ylmethyl)-S-ethyl-1,2-dihydro-2-oxopyridine;
1-(2'-cyanobiphenyl-4-ylmethyl)-6-propyl-1,2-di-hydro-2-oxopyridine;
- 25 - ~ ~ 7 ~ ~ ~ ;d l-(2'-oyanobiphenyl-4-ylmethyl)-6-pentyl-i,2-di-hydro-2-oxopyridine.
Example 3 a) A solution of 2.8 9 of 3-tert -butoxycarbonylamino-S methyl-6-butyl-1,2-dihydro-~-oxo-pyridine [m.p. 147';
obtainable by hydrogenation of ~-butyl-3-cyano-t,~-dihydro-~-oxo-pyridine with Raney-nickel in ethanol in presence of NH3 at 5 bar to yield 3-aminomethyl-6-butyl-1,2-dihydro-2-oxo-pyridine (m.p. 83 ) and reaction ~ith 2,2,8,8-tetramethyl-3,5,7-trioxa-4,6-dioxo-nonane in THF~ in 35 ml of UMF
is treated, with stirring, with 1.1 g of potassium tert.-butylate and then, after 1/2 hour, with 5.45 9 of 4'-bromomethyl-2-[1(or 2)-triphenylmethyl-lHlor 2H)tetrazol-5-yl]biphenyl (compare European patent application A2-0 3g2 3171 where it is called 1-triphenylmethyl-1H"~
although ~ithout proof of structure) and the mixture is stirred for 3 hours at 20'. 3-tert.-Butoxycarbonyl~
aminomethyl-6-butyl-1,2-dihydro-2-oxo-1-[2'-~1 triphenyl-methyl-1H-tetra701-5-yl)biphenyl-4-ylmethyl]pyridine is obtained after conventional ~orking-up (ethyl acetate).
b) A solution of 7.45 g of the product obtained according to a) in 20 ml of methylene chloride and 20 ml of methanol is treated with 20 ml of ethereal hydro-chlorid acid and the mixture is stirred for 3 hours at 20'. It is evaporated and worked up in conventional manner to qive 3-ter~.-Butoxy-carbonyl-a~inomethyl-~-butyl-1,2-dihydro-2-ox ~ 1-121-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-pyridine, m.p. 112-, after chromatrographic separation of the triphenylcarbinol formed.
The follo~ing 6-butyl-1,2-dihydro-2-oxo-1-[2'~tetrazol-5-yl)biphenyl-4-ylmethyl]pyridines are obtained analogously with the 6-butyl-1,2-dihydro-2-oxopyridines indicated in Example 2, via the corresponding 6-butyl-1,2-dihydro-2-oxo-1-[2'-(l(or 2)-triphenyl-methyl-1H(or 2H~-tetrazol-5-yl)biphenyl-4-yl-methyl]pyridines:
- 26 .- 2~7l~, 3-pyrrolidino-3-piperidino-3-succinLmido-3-phthalimido-3-b2nzamido-3-tert-butoxycarbonylamino-3-N'-butylureido-3-N'-phenylureido-3-N'-benzylureido-3-N-methylbenzamido-3-cyanomethyl 3-ethoxycarbonyLmethyl-3-(tetra~ol-5-ylmethyl)-3-acetamidomethyl- , m.p 183 (dec~ ) 3-butyramidomethyl-3-phenylacetamidomethyl-3-tert-~utoxycarbonyl~minomethyl-, ~.p. 112 3-phenoxycarbonylaminomethyl-3-ben~yloxycarbonylaminomethyl-3-ureidomethyl-3-N'-butylureidomethyl-,m.p. 275 3-N'-cyclohexylureidomethyl-, m.p. 298 3-N'-phenylureidomethyl-, m.p. 297 ~7~ 3~
-- _7 ~-N'~N'-dimethylureidomethyl-3-diethylaminomethyl-3-diisopropylaminomethyl-3-pyrrolidinomethyl-3-piperidinomethyl-3-(N-methylacetamidomethyl)-3-(N-isopropylacetamidomethyl)-3-(N-butyl-N'-methylureidomethyl)-3-(N,N'-dimethylureidomethyl)-3-(N,N',N'-trimethylureidomethyl)-3-(N-butyl-N'-phenylureidomethyl)-3-(N-benzyl-N'-methylureidomethyl)-3-(N-butyl-N- isobutoxycarbônylaminomethyl)-3-(N-isopropyl-N-benzyloxycarbonylaminomethyl)-.
~5 6-sutyl-l-(2~-cyanQbiphenyl-4-ylmethy~ ,2-di-hydro-2-oxo-3-(lH-tetrazol-5-yLmethyl)pyridine is ob-tained analogously from 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-l~2-dihydro-2-Qxo- 3-(l(or 2)-triphenylmethyl-lH(or 2H)-~etrazol 5-ylmethyl)pyridine.
Example 4 A mixture of 1 g of 1-p-aminobenzyl-6-butyl- 1,2-dihydro-2-oxopyridine, 0.6 g of phth~lic anhydride and 40 ml of CHC13 is stirred for 16 hours at 20~. The phthalic acid mono-4-~6-butyl-1,2-dihydro-2-oxopyrid-1-ylmethyL~anilide which precipitates out is filtere~ off.
Preparation of the starting material:
(a) 3 g of IIIa are dissolved in 75 ml ofmeth~nol, and a solution of 0.4 g of Na in 10 ml of methanol is added dropwise a~ 20, with stirring. The mixture is stirred for a furthex 45 min and evaporated, the residue is dissolved in 30 ml of DMF and cooled to 0, a solution of 3.7 g of p-nitrobenzyl bromide is added at this temperature and the mixture is stirred for 16 hours at 20D. It is evaporated and worked up in conven-tional manner to give 6-butyl-1-p-nitrobenzyl-1,2-dihydro-2-oxo-pyridina.
2077~
- 2~ _ (b) A solu~ion of 1.7 g of 6-butyl-1-p-nitro-ben~yl-1,2-dihydro-2-oxopyridine in 50 ml of methan~l is hydrogenated on 1.7 g of Raney Ni at 20 until the uptak~
of H2 has ceased. The mixture is filtered and evaporated to give 1-p-aminobenzyl-6 butyl-1,2-dihydro-2-oxo-pyridine.
Ex~mpl~ 5 A mixture of 2.56 g of 6-butyl-1-p-aminobenzyl-1,2-dihydro-2-oxopyridine, 3 ml of triethylamine, O.5 g of 4-dimethylaminopyridine and 120 ml of CH2Cl2 is cooled to 5 and a solution of 2.88 g of o-trifluoromethane-sulfonamidobenzoyl chloride in 20 ml of CH2Cl~ is added dxopwise. The mixture is stirred for a further 16 hours at 20, evaporated and worked up in conventional manner to give 6-butyl-1-t4-(o-triiluoromethanesulfonamido-benzamido~benzyl]-1,2-dihydro-2-oxopyridine.
Example 6 A mixture of 2.85 g of 6-butyl-1-p-carboxybenzyl-1,2-dihydro-2 oxopyridine, 12 g of thionyl chloride and 35 ml of CHCl3 is boiled for 6 hour3 and evaporated. The crude acid chloride obtained is freed from thionyl chloride residues by dis~olution several tLmes in toluene and evaporation, and is dissolved in 50 ml of THF. This solution is added dropwise to a solution of 1.7 g of anthranilic acid and 008 g of NaOH in 100 ml of water and the mixture is stirred for 24 hours and acidified tG pH
5 with hydrochloric acid. 6-Butyl-l-C4 (2-carboxyanilino-c~rbonyl)benzyl]-1,2-dihydro-2-oxopyridine is obtained after conventional working-up.
Preparation of the starting materials:
~a) IIIa is reacted with p-bromomethylbenzo-nitrile analogously to Example 1 to give 6-butyl-1-p-cyanobenzyl-1,2-dihydro-2-oxopyridine after chromato-graphy on ~ilica gel (methyl tert-butyl e~her/methanol).
(b) A mixture of 1 g of 6-butyl-1-p-cyanobenzyl-1,2-dihydro-2~oxopyridine, 0.7 g of KOH, 20 ml of ethanol ~7~
and 5 ml of water i~ hoiled for 24 hours, with stirring, evaporated, dissolved in water and acidified with hydro-chloric acid. The 6-butyl-1-p-carboxyben~yl-1,2~dihydro-2-oxopyridine which precipitates out is filtered off and washed with water.
Example 7 A mixture of 1.19 g of o-cyanophenol/ 0.75 g of CO3 and 10 ml of DMF is stirred for 0.S hour. A
solution of 3.34 g of 1-p-bromomethylbenzyl-6-butyl-1,2-dihydro-2-oxopyridine (obtainable by reaction of IIIa with p-benzyloxymethylbenzyl bromid~ to give 1-benzylo~y-methylbenzyl-6-butyl-1,2-dihydro-2-oxopyridine, hydrogenolysis to gi~e the 3-p-hydroxymethylbenzyl compound, and reaction with PBr3) in 20 ml of DMF is added dropwis~ and the mixture i5 heated at 90 for 8 hours and evaporated to give 6-butyl-1-(4-o-cyanophenox~methyl~
benzyl)-1,2-dihydro 2 oxopyridine after conventional working-up.
Example 8 A mixture of 2.57 g of 6-butyl-1-p-hydroxybenzyl-1,2-dihydro-2 oxopyridine (obtainable from IIIa and p-hydroxybenzyl bromide), 0.5 g of CH30Na and 40 ml of DMSO
is stisred for 0.5 hour. A solution of 2.2 g of o-cyanobenzyl bromide in 15 ml of ~MSO i9 added dropwise and the mixture is stirred for 16 hours at 20 and evaporated to give ~-bu~yl~ 4-o-cyanobenzyloxybenzyl)-1,2-dihydro-2-o~opyridine after conventional working-up~
Exampie g A mixture of 404 mg of 6-butyl-1-[4-(2-methoxy-carbonylanilinocarbonyl)ben~yl]-1,2-dihydro-2-oxopyri-dine, 10 ml of 0.1 N aqueou~ NaOH solution and 17 ml of THF is left to stand for 48 hours at 20 . The THF is evaporated off, the residue i~ acidified with HCl and extracted with methylene chloride a~d the extract is dried over Na2SO4 to give 6-butyl-1-[4-(2-carboxy-anilinocarbonyl)ben~yl]-1,2-dihydro-2-oxopyridine af ter evaporation.
The following are obtained analogously from the corresponding methyl or ethyl ester :
5-butyl-1,2-dihydro-2-oxo-1-(2'-cyanobiphenyl-4-ylmethyl)pyridine-3-carboxylic acid 6-butyl-1,2-dihYdro-2-ox~-1-(2'-cyanobiphenyl-4-ylmethyl)pyTidine-3-acetic acid 6-butyl 1-~2~-(tetrazol-5-yl)biphenyl-4-ylmethyl~-1,~-dihydro-2-oxopyridine-3-acetic acid.
Example 1o ~0 A mixture of 400 mg of6-butyl-3-cyan ~ thyl-1-(2~-methoxycarbo~ylbiphe~yl-4-ylmethyl)-1,2-dihydro-2-oxopyridine and 2~2 ml of 1 N aq~eous ROH ~olu~ion is boiled for 3 hours, cooled and acidified with hydro-chloric acid. 6-Butyl-3-cOEb~y~thyl-1-(2'-carboxybiphenyl-4-ylmethyl)-1,2-dihydrc-2-oxopyridine i5 obtain~d afte~ conventional ~orking-up.
Example 11 A mixture of 47Z mg of 3-tert.-butoxy-carbonylaminomethyl-6-butyl-1-(2'-cyanobi-30 phenyl-4-ylmet.hyl)-1,2-dihydro-2-oxopyridine, 206 mg of trLmethyltin azide a~d 12 ml of xylene i5 boiled for 96 hours; a further 0.2 g of azide is added after 48 hour~.
The mixture is cooled, treated with e~hereal hydrochloric acid and evaporatedA Chromatography of the residue (silica gel; methylene chloride/methanol 95:5) yields 3-tert,butoxycarbonylaminomethyl-6-butyl-1,2-dihydro-2-oxo-~ etraæol-5-yl~-biphenyl-4-ylmethy ~pyridine; m.p.105.
The corresponding K salt is prepared therefrom in conven-tional manner.
2 ~ 7 ~
Exampl~ 12 6-Butyl-1,2-dihydro-2-oxo-3-ttetra~ol-5-yl)-l-f2'-~tetraz~l-5-yl)biphenyl-4-ylmethy ~pyridine, m.p. ~59 (dec.), Rf 0.1 (7:3), is obtained from 6-butyl-3-cyano-1-(2'-cyan~biphenyl-4-ylmethyl)-1,2-dihy-dro-2-oxopyridine analogously to Example 11, except that 2 equivalents of trimethyltin a~ide are used.
Dipotassium salt, m.p. 235~.
6-Butyl-3-cyano-1,2-dihydro-2-oxo-1- ~ '-(tetrazol-5-yl)biphenyl-4-ylmethyl7pyridine is cbtained as a by-product (separable by chromatography).
6-~ethyl-l,2-dihydro-2-oxo-5-propyl-3-(tetrazol-~-yl)-l-~ 2 ' - ( tetra zol - 5 -yl )biphenyl-4-ylmethyl~pyridine can be prepared analogously from 3-oyano-l-(2'-cyano-biphenyl-4-ylmethyl)-6-methyl-l,2-dihydro-2-oxo-5-propyl-pyridine.
Example 13 A mixture o 472 mg of 3-tert~-butoxy-carbonyl_ amino~ethyl-6-butyl-1-(2'-cyanGbiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridi~, 700 mg of NH~Cl, 700 mg of NaN3 and 4 ml of D~Y is stirred for 36 hours at 120. It is cooled, the NaCl formed is filtered off and the filtrate is evaporated and worked up with aqueous hydrochloric acid/methylene chloride in conven-tional manner to give 6-butyl-l,2-dihydro-2-oxo- l-[2'-~ tetrazol-5-yl)biphenyl 4-ylmethyl~pyridine, m.p. 105.
Example 14 a) A solution of l g of 6-butyl~l-(2'-nitrobiphenyl-4-ylmethyl)-1,2 dih~dro-2-oxopyridi~e in 30 ml of ethanol 3~ is hydrogenated on l g of Raney Ni at 20~ until the uptake of H2 has ceased. The mixture is filtered and evaporated to give l-(2'-aminobiphenyl-4-ylmethyl~
butyl-l,2-dihydro-2-oxopyridine.
~rl7 D.L ~
~1 A solution of 2.82 g of trifluoromethanesulfonic anhydride in 10 ml of CH2C12 is added dropwise to a solution of 3.32 g of l-(2~-aminobiphenyl-4-ylmethyl)-6 butyl-1,2-dihydro-2-oxopyridine and 1,01 g of triethyl-amine in 30 ml of CH2Cl2 at -50 to -60. The mixture is left to warm up to 20 and poured into dilute acetic acid to give 6-butyl-1-(2'-trifluoromethanesulfonamidobi-phenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine after conventional working-up.
10 Example 15 15 mg of Na~4 are added at 20 to a solution of 370 mg of 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-3 formyl-1,2-dihydro-2-oxopyridine in 5 ml of isopropa~
nol, with stirring. After further tirring (1 hour), 15 dilute hydrochloric acid is a~ded dropwi~e until the evolution of Hz ha~ cea~ed, and the mixture i~ evaporated.
6-Butyl-1-(2' cyanobiphenyl-4-ylmethyl)-3-hydroxy~ethyl-1,2-dihydro-2-oxopyridine i~ obtained after conventional working-up.
20 Example 16 0.07 ml of bromine is added dropwis at 0~ to a solution of 280 mg of NaOH in 6 ml of water, with stirring. 360 mg of 6-butyl-3-carbamoyl-1-(2~-cyano-biphenyl-4-ylmethyl)-1,2-dihydro~2-oxopyridine are then 25 added. The mixture i5 heated for 3 hour~ on a steam bath, acidified with 6 N hydrochloric acid and stirred for a further 30 minutes. It i~ neutrali~ed with 10% RHC03 solution, cooled and worked up in conventional manner to give 3-amino-6-buty~ (2~-cyanobiphenyl-4- ylmethyl) 30 1,2-dihydro-2-oxopyridine.
Example 17 A solution of 1 g of 3-~ert-butoxycarbonylamino-6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl~-1,2-dihydro-2-oxopyridine in 2a ml of a 4 N HCl solution in dioxane i5 stirred for 1 hour a~ 20 and then evaporated to give 3-amino-6-butyl~ 2'~cyanobiphenyl-4-ylmethyl)-1,2-dLhydro-2-oxopyridine in the form of the hydrochloride.
2 0 7 ~
- 33 ~
E~ample 1B
A suspension of 370~mg of 6-butyl~ 2'-cyano~
biphenyl-4-ylmethyl)-3-formyl-1,2-dihydro-2-oxopyridine, 770 mg of ammonium acetate, 61 mg of NaBH3CN and 400 mg of S a powdered 3 ~ molecular sieve in lO ml o isopropanol i~
stirred under argon for 3 days at 20. It is filtered, the material on the filter is washed with methanol and the filtrate is evaporated. 3-Aminomethyl-6-butyl~1-(2'-cyanobiphenyl-4-ylmethyl)-l,2-dihydro-2-oxopyridine is obtained after conventional working-up (sodium hydroxide solution/methylene chloride), m.p. 118.
3-~nome~yl-6-butyl-1,2~hydro-2-oxo~ '-(tetra-zol-5-yl)biph2nyl-4-ylmethyl]pyridine i~ obtained ana-logously from 6-butyl-3-formyl-l,2-dihydro-2-oxo-l-[2'-(tetrazol-5~yl)biphenyl-4-ylmethyl]pyridine, decom~ition starting at 7S.
E~ample l9 A mixture of 3.7 g of 6-butyl-l-(2'-cyanobi-phenyl-4-ylmethyl)-3- f or~yl~ dihydro-2-oxopyridine, 0.59 g of isopropylamine and 3.55 g of titanium tetra-isopropoxide is c~irred for 2 hours at 20 under N2.
10 ~1 of absolute ethanol and the~ 6lO mg of NasH3CN are added, ths ~ixture is stirred for a further 20 hours, 2 ml of water are then added and ~he mixture is filtered.
The filtrate i~ evaporated. 6-Butyl-l-(2'-cyanobiphenyl-- 4-yl~ethyl)-3-i~opropylaminomethyl-l,2-dihydro-2-oxo-pyridine is obtained after conven~ional working-up.
The following are ob~ained analogously with butylamine or benzylamine:
6-butyl-3-butylaminomethy~ (2~-cyanobiphenyl-4 ylme~hyl)-l,2-dihydro 2-oxopyridine 3-benzylaminomethyl-6-butyl-l-t2~-cyanobiphenyl-4-ylmethyl~-l,2-dihydro-2-oxopyridine, oil, Rf 0.15 (dichloromet:hane/methanol 95:5) and the following are obtained from 6-butyl-3-formyl-l-[2'-(tetrazol-5-yl)biphenyl-4-ylmethyl]-l,2-dihydro-2-2~7~:~2 ~ 34 -oxopyridine:
5-butyl-3-i~opropyl~minomethyl-1-[2~-(tetrazol-5-yl)biphenyl-4-ylmethyl3-1,2-dihydro-2-oxopyridine 6-butyl-3-butylaminomethyl-1-[2'-(tetrazol~5-yl)-biphenyl-4-ylmethyl3-1,2-dihydro-2-oxopyridine 3-benzylaminomethyl-6-butyl-1-[2'-(t~trazol-5-yl)biphenyl-4-ylmethyl]-1,2-dihydro-2-oxopyridine.
Example 20 6-Butyl~ 2'-~yanobiphenyl-4-ylmethyl)-3-iso-propylamino-1,2-dihydro-2-oxopyridine is obtained ana-logously to Example 19 from 3-~ino-6-butyl-1-(2'-c~anobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine and acetone/tita~ium tetraisopxopoxide/NaB~3CN.
The following are obtained analogously with butyraldehyde, ben~aldehyde or hexafluoroacetone from the corresponding 3-amino or 3-aminomethyl compounds:
6-butyl-3-butylamino-1-(2'-cyanobiphenyl-4 yl-mathyl~-1,2-dihydro-2-oxopyridine 3-benzylamino~6-butyl-1-(2'-cyanobiphenyl-4-yl methyl) 1,2-dihydro-~-oxopyridine 6-butyl-3~ 1,3,3,3-hexafluoro-2-propyl~mino)-1-12'~cy~nobiphenyl-4-ylmethyl)~l, 2 -dihydro-2 -oxopyridine 6-butyl-3-(1,1,1,3,3,3-hexafluoro-2-propyla~ino-m~thyl)-1-(2~-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-o~opyridine 3-benzylamino-6-butyl-1,2-dihydro-2-oxo-1-[2'-(tetrazol-5-yl)biphenyl-4-ylmethyl]pyridine 6-butyl-3-(1,1,1,3,3,3-hexafluoro-2-propylamino)-1,2-dihydro-2-oxo-1-[2'-(tetra~ol-5-yl)biphenyl-4-ylmethyl3pyridine 6-butyl-3-(1,1,1/3,3,3-hexafluoro-2-propylamino-methyl)-1,2-dihydro-2-oxo-1-[2'-(tetrazol-5-yl)-biphenyl~4-ylmethyl]pyridine.
2~77~ ~
~xample 21 Analogously to Example 1, there are obtained from IIa with 6-butyl-1.2-dihydro-3-methyl~ulfonylaminomethyl-, -3-trifluorom~thyl-sulfonylaminomethyl-, -3-phenyl~ulfonyla~inomethyl- ~r -3-p-t~lyi-sulfonylaminomethyl-2-oxo-pyridine the follo~ing 6-butyl~ '-oyano-biphenyl-4-yl~-methyl-1,2-dihydro-2-oxo-pyridines:
3-methylsulfonylaminomethyl-, m p 59 3-trifluoromethyl~ulfonylaminomethyl-~-phenylsulfonylaminomethyl-3-p-tolylsulfonylaminomethyl-, m p.119 Example 22 Analogously to Example 11, the following 6-butyl-1-[2'-(~-tetrazolyl)-biphenylyl-4-~ethyl~-1,2-dihydro-2-oxo-pyridines are obtained from the 2'cyano-biphenyl-4-yl compounds mentioned in Example 21 ~ith trir~ethyltin azide:
3-methylsulfonylaminomethyl-3-trifluoron~thylsulfonylaminomethyl-3-phenylsulfonylaminomethyl-3-p-tolylsulfonylamino~ethyl-.
2 ~1 7 7 ~ 1 r~
The following Example~ relate to pharmaceutical formulations containing active ingredients of formula I
or their salts.
Example A: Tablets and coated tablets Tablets of the following compo~ition are produced by pressing in conventional manner and, where necessary, are provided with a conventional ~ucrose- based coating:
Active ingredient of formula I100 mg 10 Microcrystalline cellulose278.8 mg Lactose 110 mg Maize ~tarch ll mg Magnesium steara~ 5 mg Finely divided silicon dioxido0.2 ~q Example E: ~ rd gelatin cap~ul~
Conventional two-part hard gel~tin capsules are each filled with Active ingredient of formula I100 mg Lactose 150 mg 20 Cellulose 50 mg Magn~sium ~tearate S mg ~xample C: Soft gelatin capcule~
Conventional soft gelatin capsule~ are filled with a mixture consisting in each case of 50 mq of active ingredient of formula I and 250 mg of olive oil.
Example D: Ampoules A solution of 200 g of active ingredient of formula I in 2 kg of propane-1,2-diol is made up to 10 1 ~ith water and filled into ampoule~ 80 that each ampoule contains 20 mg of active ingredient.
with 6-butyl-1~2-dihydro-2-oxo-3-trimethylacetamido-pyridine:
6-buty~ 2~-cyano~iphenyl-4-ylme~hy~ 2 dihydro-2-oxo-3-trLmethylacetamidopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-benzamidopyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-ben~amidopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-tert-butoxycarbonyl-aminopyridlne:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl~-1,2-dihydro-2-oxo-3-tert-butoxycarbonylaminopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-N'-butylureidopyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-N'-butylureidopyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-N'-phenylureidopyridine, 6-butyl 1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-N'-phenylureidopyridine;
with 6-butyl~1,2 dihy~r~ 2 oxo-3-N'-benzylureidopyridine:
6-butyl~ 2'-cyanobiph~nyl-4-ylmethyl)~1,2~dihy~ro ~-oxo-3-~'-ben~ylureidopyridine;
with 6-butyl~1,2-dihydro-2-oxo-3 N-methylbenzamidopyTi-dine:
6-butyl-1-(2'-cyanobiphenyl-4~ylmethyl)-1,2-dihydro-2-oxo-3~N methylbenzamidopyridine;
with 6-butyl-112-dihydro-2~oxo~3-methylpyridine ~obtain-able by hydrogenolysi~ of ~-ac~togymethyl-2-benzyl-oxy-~-butylpyridine on Pd/C in ethanol at 20 and 1 bar~:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl~-1,2-dihydro-~-oxo-3-methylpyridine; m.p. 126~; Rf 0.4;
with 6-butyl-1~2-dihydro-2-oxo-3-fluoromethylpyridine:
6-butyl~l (2'-cyanobiphenyl-4-ylmethyl)-1,~-dihydro-2-oxo-3-fluoromethylpyxidine;
with 6-butyl-1,2-dihydro-2-oxo-3-chlorome~hylpyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-chloromethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-cyanomethylpyridine:
2 0 ~
' 6-bu~yl~ cyanobiphenyl-4-ylmethyl)-l,2-dihydro-2-oxo-3-cyanomethylpyridine;
with ethyl 6-b~yl-1,?-dihydro-2-oxopyridine-3-acetate:
ethyl 6-~u~yl-1-(2'-cyanobiphenyl-4-ylmethyl~-1,2-S dihydro-2-oxopyridine-3-acetate;
with 6-butyl-1,2-dihydro-2-oxo-3-methoxymethylpyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-methoxym~thylpyridine;
with 6-butyl-l,2-dihydro-2-oxo-3-isopropoxymethylpyri-dine:
6-butyl-1-(2'-cyanobiphenyl-4-yLmethyl)-1,2-dihydro-2-oxo-3-isopr~poxymethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-butoxymethylpyridine ~oil; obtainable by reaction of IIIb with benzyl chloride in the presence of Ag20 in toluene (boiling for 24 hours~ to give 2-benzyloxy-6-butyl-3-cyano-pyridine ~oil), hydrolysis with aqueous-ethanolic KOH (boiling fo~ 48 hours~ to give 2-benzyloxy-6-butylnicotinic acid, reduction with LiAlH4 in THF to gi~e 2-benzyloxy-6-butyl-3-hydIoxymethylpyridine~
alXylation with butyl iodide in THF in the presence of NaH to give 2-benzyloxy-6-butyl-3-butoxymethyl-pyridine, and hydrogenolysis on 5~ Pd/C in methanol]~ -6-butyl-1-~2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-butox~methylpyridine; Rf 0.2;
with 6-butyl-1,2-dih~dro 2-oxo-3-benzyloxymethylpyridine:
6-butyl-1-(2~ cyanobiphenyl-4-yLmethy~ 2-dihydro 2-oxo-3-benzyloxymethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-acetamidomethylpyridine:
6-butyl-1-(2'-c,yanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-acetamidomethylpyridine,m.p. 150;
with 6-butyl-1,2-dihydro~2-oxo-3-butyramidomethylpyri-dine:
6-butyl-1-(2'~cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-butyramidomethylpyridine;
with 5-butyl-1,2-dihydro-2-o~o-3-phenylacetamidomethyl-pyridine:
20~7~ ~ ~
6-~utyl~ 2~-~ydnQbiphenyl-4-ylmethyl)-1,2-dihydLo-2-oxo-3-phenyl~cetamidomethylpyridine;
wi~h 6-butyl-1,2-dihydro-2-oxo-3-tert-butoxycarbonyl-aminomethylpyridine:
6-b~tyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2 dihydro-2-oxo-3-tert-butoxycarbonylaminomethyl pyridine,~.p.105~;
with 6-butyl-1,2-dihydro-2-oxo-3-phenoxycarbonylamino-methylpyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-phenoxyca~bonylaminomethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-benzyloxycarbonyl,~mino-methylpyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl~-1,2-dihydro-2-oxo-3-benzyloxycarbonylaminomethylpyridine oil, RfO.58 (ethylacetate~hexane 1:1);
with 6-butyl-1,2~dihydro-2-oxo-3-ureidomethylpyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylm~thyl) 1,2~dihydro-2-oxo-3-ureidomethylpyridine, m p.166, with 6-butyl-1,2-dihydro-2-oxo-3-~N'-butylureidomethyl)-pyridine:
6-butyl-1-(2'-cyanobiphenyl-4-yL~ethyl)-1,2-dihydro-2-oxo-3-(N'-butylureidomethyl)pyridine! m.p. 61, with 6-butyl-1,2-dihydro-~-oxo-3-(N~-cyclohexylureido-methyl~pyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl) 1,~-dihydro-2-oxo-3-(N'-cyclohexylurcidomethyl)pyridine,m.p.g8;
with 6-butyl-1,2-dihydro-2-oxo-3-(N'-phenylureidomethyl)-pyridine:
6-butyl-1-(2'-cyanobiphenyl-4 ylmethyl ) -1, 2-dihydro-2-oxo-3-(N'-phenylureidomethyl)pyridine,m.p.89-;
with 6-butyl-l~2-dihydro-2-oxo-3-( N ', N '-dimethylureido-methyl)pyridine:
6-butyl~ 2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydxo-2-oxo-3-(N',N'-dimethylureidomethyl)pyridine,m.p.60;
with 6-butyl-1,2-dihydro-2-oxo-3-diethylaminomethyl-pyridine:
6-butyl-1-(2'-cyanobiphenyl-4 ylmethyl)-1,2-dihydro-2-oxo-3-diethylaminome~hylpyridine;
~77~
- ?3 -with 6 butyl-1,2-dihydro-2 oxo-3-diisopropylaminomethyl-pyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylme~hyl)~1,2-dihydro-2-oxo-3-diisopropylaminomethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-pyrrolidinomethylpyri-dine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl) 1,2-dihydro-2-oxo-3-pyrrolidinomethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-piperidinomethylpyri-dine:
6-butyl-1 ~2'-cyanobiphenyl-4-yLmethyl)-1,2-dihydro-2-oxo-3-piperidinomethylpyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-(N-methylacetamido-methyl~pyridine:
5-butyl-1-(2'-cyanobiphenyl-4-yLmethyl)-1,2-dihydro-2-oxo- 3-(N-methylacetamidomethyl)pyridine;
with ~-butyl-1~ 2-dihydro-~-oxo-3-(N-isopropylace~amido-methyl)pyridine:
6 butyl-1~ cyan~biphenyl-4-ylm~thyl)-1 J 2-dihydro 2-oxo-3-~N-i~opropylacatamidomethyl)pyridine with 6-butyl-1,2-dihydro-2-oxo-3-~N-butyl-N'-methyl-ureidomethyl)pyridine:
6-butyl-1-(2.'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-(N-butyl-N'-methylureidomethyl)pyridine;
with 6-butyl 1,2-dihydro-2-oxo-~-(N,N'-dimethylureido-ethyl)pyridine:
6-butyl-1-(2' -cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-(N,N'-dimethylureidomethyl)py~idine;
with 6-butyl-1,2-dihydro-2 oxo-3-(N,N',N'-trimethyl-ureidomethyl)pyridine:
6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-(N,N',N'-trimethylureidomethyl)pyridine;
with 6-butyl-1,2-dihydro-2-oxo-3-(N-butyl-N'-phenyl ureidomethyl)pyridine:
6-butyl-1-(2'-cyanobiphenyl-4 ylmethyl)-1,2-dihydro-2-oxo-3-(N-butyl N'~phenylureidomethyl)pyridine;
with 6-butyl 1,2 dihydro-2-oxo-3-~N-benzyl-N'-methyl-ureidomethyl~pyridine:
~77'~h 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1~2-dLhydro~
2-QXo- 3-(N-benzyl-N'-methylureidomethyl)pyridine;
with 6-butyl-1,2 dihydro-2-oxo-3-(N-butyl-N-iSobutoxy-carbonylaminomethyl)pyridine:
6-butyl-1-(2~-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxo-3-(N-butyl-N-isobutoxycarbonylaminomethyl) pyridine;
with 6-butyl-1,2-dihydro~2-oxo-3-(N-isopropyl-N-benzyl-oxycarbonylaminomethyl)pyridine:
6-butyl-1-(2'-cyanobiphenyl-4-y~methyl)-1, 2-dihydro-2-oxo-3-(N-isopropyl-N-benzyloxycarbonylamino-methyl)pyridine;
with 4-methyl-1l2-dihydro-2-oxopyridine:
4-methyl-1,2-dihydro 2~oxo-1-(2'-cyanobiphenyl-4-ylmethyl)pyridine; Rf 0.1, with 1,2-dihydro-2-oxo-6-phenylpyridine:
1-(2'-cyanobiphenyl-4-ylmethyl) 1,2-dihydro-2-o~o-6-phenylpyridine; Rf 0.~;
with methyl 6 isobu~yl-1,2-dihydro-2-oxopyridine-3-carboxylate (obtainablP analogou~ly to IIIa from 4-methylpantan-2~one via 1-hydroxy-5-methylhexen-1-one, 6-isobutyl-1~2-dihydro-2-oxo-3-cyanopyridine and 6-isobutyl- 1,2-dihydro-2-oxopyridine-3-carboxylic acid):
methyl 1~ cyanobiphenyl-4-ylmethyl)-6-isobutyl-1,2-dihydro-2-oxopyridine-3-carboxyla~e; R 0.5;
with 3-cyano-6-methyl-1/2-dihydro-2-oxo-5-propylpyridine (formed a~ a by product in the prepar~tion of IIIb):
3-cyano~ 2'-cyanobiphenyl 4-methyl)-6-methyl-1,2-dihydro-2-oxo~5-propylpyridine; m.pO 186;
with 6Imethyl-~ 6-ethyl-, Ç-propyl- or 6-pentyl-1,2-dihydro-2-oxopyridine:
1~2'-cyanobiphenyl-4-ylmethyl)-6-methyl 1,2-di-hydro-2-oxopyridine;
1-(2'-cyanobiphenyl-4-ylmethyl)-S-ethyl-1,2-dihydro-2-oxopyridine;
1-(2'-cyanobiphenyl-4-ylmethyl)-6-propyl-1,2-di-hydro-2-oxopyridine;
- 25 - ~ ~ 7 ~ ~ ~ ;d l-(2'-oyanobiphenyl-4-ylmethyl)-6-pentyl-i,2-di-hydro-2-oxopyridine.
Example 3 a) A solution of 2.8 9 of 3-tert -butoxycarbonylamino-S methyl-6-butyl-1,2-dihydro-~-oxo-pyridine [m.p. 147';
obtainable by hydrogenation of ~-butyl-3-cyano-t,~-dihydro-~-oxo-pyridine with Raney-nickel in ethanol in presence of NH3 at 5 bar to yield 3-aminomethyl-6-butyl-1,2-dihydro-2-oxo-pyridine (m.p. 83 ) and reaction ~ith 2,2,8,8-tetramethyl-3,5,7-trioxa-4,6-dioxo-nonane in THF~ in 35 ml of UMF
is treated, with stirring, with 1.1 g of potassium tert.-butylate and then, after 1/2 hour, with 5.45 9 of 4'-bromomethyl-2-[1(or 2)-triphenylmethyl-lHlor 2H)tetrazol-5-yl]biphenyl (compare European patent application A2-0 3g2 3171 where it is called 1-triphenylmethyl-1H"~
although ~ithout proof of structure) and the mixture is stirred for 3 hours at 20'. 3-tert.-Butoxycarbonyl~
aminomethyl-6-butyl-1,2-dihydro-2-oxo-1-[2'-~1 triphenyl-methyl-1H-tetra701-5-yl)biphenyl-4-ylmethyl]pyridine is obtained after conventional ~orking-up (ethyl acetate).
b) A solution of 7.45 g of the product obtained according to a) in 20 ml of methylene chloride and 20 ml of methanol is treated with 20 ml of ethereal hydro-chlorid acid and the mixture is stirred for 3 hours at 20'. It is evaporated and worked up in conventional manner to qive 3-ter~.-Butoxy-carbonyl-a~inomethyl-~-butyl-1,2-dihydro-2-ox ~ 1-121-(tetrazol-5-yl)-biphenyl-4-ylmethyl]-pyridine, m.p. 112-, after chromatrographic separation of the triphenylcarbinol formed.
The follo~ing 6-butyl-1,2-dihydro-2-oxo-1-[2'~tetrazol-5-yl)biphenyl-4-ylmethyl]pyridines are obtained analogously with the 6-butyl-1,2-dihydro-2-oxopyridines indicated in Example 2, via the corresponding 6-butyl-1,2-dihydro-2-oxo-1-[2'-(l(or 2)-triphenyl-methyl-1H(or 2H~-tetrazol-5-yl)biphenyl-4-yl-methyl]pyridines:
- 26 .- 2~7l~, 3-pyrrolidino-3-piperidino-3-succinLmido-3-phthalimido-3-b2nzamido-3-tert-butoxycarbonylamino-3-N'-butylureido-3-N'-phenylureido-3-N'-benzylureido-3-N-methylbenzamido-3-cyanomethyl 3-ethoxycarbonyLmethyl-3-(tetra~ol-5-ylmethyl)-3-acetamidomethyl- , m.p 183 (dec~ ) 3-butyramidomethyl-3-phenylacetamidomethyl-3-tert-~utoxycarbonyl~minomethyl-, ~.p. 112 3-phenoxycarbonylaminomethyl-3-ben~yloxycarbonylaminomethyl-3-ureidomethyl-3-N'-butylureidomethyl-,m.p. 275 3-N'-cyclohexylureidomethyl-, m.p. 298 3-N'-phenylureidomethyl-, m.p. 297 ~7~ 3~
-- _7 ~-N'~N'-dimethylureidomethyl-3-diethylaminomethyl-3-diisopropylaminomethyl-3-pyrrolidinomethyl-3-piperidinomethyl-3-(N-methylacetamidomethyl)-3-(N-isopropylacetamidomethyl)-3-(N-butyl-N'-methylureidomethyl)-3-(N,N'-dimethylureidomethyl)-3-(N,N',N'-trimethylureidomethyl)-3-(N-butyl-N'-phenylureidomethyl)-3-(N-benzyl-N'-methylureidomethyl)-3-(N-butyl-N- isobutoxycarbônylaminomethyl)-3-(N-isopropyl-N-benzyloxycarbonylaminomethyl)-.
~5 6-sutyl-l-(2~-cyanQbiphenyl-4-ylmethy~ ,2-di-hydro-2-oxo-3-(lH-tetrazol-5-yLmethyl)pyridine is ob-tained analogously from 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-l~2-dihydro-2-Qxo- 3-(l(or 2)-triphenylmethyl-lH(or 2H)-~etrazol 5-ylmethyl)pyridine.
Example 4 A mixture of 1 g of 1-p-aminobenzyl-6-butyl- 1,2-dihydro-2-oxopyridine, 0.6 g of phth~lic anhydride and 40 ml of CHC13 is stirred for 16 hours at 20~. The phthalic acid mono-4-~6-butyl-1,2-dihydro-2-oxopyrid-1-ylmethyL~anilide which precipitates out is filtere~ off.
Preparation of the starting material:
(a) 3 g of IIIa are dissolved in 75 ml ofmeth~nol, and a solution of 0.4 g of Na in 10 ml of methanol is added dropwise a~ 20, with stirring. The mixture is stirred for a furthex 45 min and evaporated, the residue is dissolved in 30 ml of DMF and cooled to 0, a solution of 3.7 g of p-nitrobenzyl bromide is added at this temperature and the mixture is stirred for 16 hours at 20D. It is evaporated and worked up in conven-tional manner to give 6-butyl-1-p-nitrobenzyl-1,2-dihydro-2-oxo-pyridina.
2077~
- 2~ _ (b) A solu~ion of 1.7 g of 6-butyl-1-p-nitro-ben~yl-1,2-dihydro-2-oxopyridine in 50 ml of methan~l is hydrogenated on 1.7 g of Raney Ni at 20 until the uptak~
of H2 has ceased. The mixture is filtered and evaporated to give 1-p-aminobenzyl-6 butyl-1,2-dihydro-2-oxo-pyridine.
Ex~mpl~ 5 A mixture of 2.56 g of 6-butyl-1-p-aminobenzyl-1,2-dihydro-2-oxopyridine, 3 ml of triethylamine, O.5 g of 4-dimethylaminopyridine and 120 ml of CH2Cl2 is cooled to 5 and a solution of 2.88 g of o-trifluoromethane-sulfonamidobenzoyl chloride in 20 ml of CH2Cl~ is added dxopwise. The mixture is stirred for a further 16 hours at 20, evaporated and worked up in conventional manner to give 6-butyl-1-t4-(o-triiluoromethanesulfonamido-benzamido~benzyl]-1,2-dihydro-2-oxopyridine.
Example 6 A mixture of 2.85 g of 6-butyl-1-p-carboxybenzyl-1,2-dihydro-2 oxopyridine, 12 g of thionyl chloride and 35 ml of CHCl3 is boiled for 6 hour3 and evaporated. The crude acid chloride obtained is freed from thionyl chloride residues by dis~olution several tLmes in toluene and evaporation, and is dissolved in 50 ml of THF. This solution is added dropwise to a solution of 1.7 g of anthranilic acid and 008 g of NaOH in 100 ml of water and the mixture is stirred for 24 hours and acidified tG pH
5 with hydrochloric acid. 6-Butyl-l-C4 (2-carboxyanilino-c~rbonyl)benzyl]-1,2-dihydro-2-oxopyridine is obtained after conventional working-up.
Preparation of the starting materials:
~a) IIIa is reacted with p-bromomethylbenzo-nitrile analogously to Example 1 to give 6-butyl-1-p-cyanobenzyl-1,2-dihydro-2-oxopyridine after chromato-graphy on ~ilica gel (methyl tert-butyl e~her/methanol).
(b) A mixture of 1 g of 6-butyl-1-p-cyanobenzyl-1,2-dihydro-2~oxopyridine, 0.7 g of KOH, 20 ml of ethanol ~7~
and 5 ml of water i~ hoiled for 24 hours, with stirring, evaporated, dissolved in water and acidified with hydro-chloric acid. The 6-butyl-1-p-carboxyben~yl-1,2~dihydro-2-oxopyridine which precipitates out is filtered off and washed with water.
Example 7 A mixture of 1.19 g of o-cyanophenol/ 0.75 g of CO3 and 10 ml of DMF is stirred for 0.S hour. A
solution of 3.34 g of 1-p-bromomethylbenzyl-6-butyl-1,2-dihydro-2-oxopyridine (obtainable by reaction of IIIa with p-benzyloxymethylbenzyl bromid~ to give 1-benzylo~y-methylbenzyl-6-butyl-1,2-dihydro-2-oxopyridine, hydrogenolysis to gi~e the 3-p-hydroxymethylbenzyl compound, and reaction with PBr3) in 20 ml of DMF is added dropwis~ and the mixture i5 heated at 90 for 8 hours and evaporated to give 6-butyl-1-(4-o-cyanophenox~methyl~
benzyl)-1,2-dihydro 2 oxopyridine after conventional working-up.
Example 8 A mixture of 2.57 g of 6-butyl-1-p-hydroxybenzyl-1,2-dihydro-2 oxopyridine (obtainable from IIIa and p-hydroxybenzyl bromide), 0.5 g of CH30Na and 40 ml of DMSO
is stisred for 0.5 hour. A solution of 2.2 g of o-cyanobenzyl bromide in 15 ml of ~MSO i9 added dropwise and the mixture is stirred for 16 hours at 20 and evaporated to give ~-bu~yl~ 4-o-cyanobenzyloxybenzyl)-1,2-dihydro-2-o~opyridine after conventional working-up~
Exampie g A mixture of 404 mg of 6-butyl-1-[4-(2-methoxy-carbonylanilinocarbonyl)ben~yl]-1,2-dihydro-2-oxopyri-dine, 10 ml of 0.1 N aqueou~ NaOH solution and 17 ml of THF is left to stand for 48 hours at 20 . The THF is evaporated off, the residue i~ acidified with HCl and extracted with methylene chloride a~d the extract is dried over Na2SO4 to give 6-butyl-1-[4-(2-carboxy-anilinocarbonyl)ben~yl]-1,2-dihydro-2-oxopyridine af ter evaporation.
The following are obtained analogously from the corresponding methyl or ethyl ester :
5-butyl-1,2-dihydro-2-oxo-1-(2'-cyanobiphenyl-4-ylmethyl)pyridine-3-carboxylic acid 6-butyl-1,2-dihYdro-2-ox~-1-(2'-cyanobiphenyl-4-ylmethyl)pyTidine-3-acetic acid 6-butyl 1-~2~-(tetrazol-5-yl)biphenyl-4-ylmethyl~-1,~-dihydro-2-oxopyridine-3-acetic acid.
Example 1o ~0 A mixture of 400 mg of6-butyl-3-cyan ~ thyl-1-(2~-methoxycarbo~ylbiphe~yl-4-ylmethyl)-1,2-dihydro-2-oxopyridine and 2~2 ml of 1 N aq~eous ROH ~olu~ion is boiled for 3 hours, cooled and acidified with hydro-chloric acid. 6-Butyl-3-cOEb~y~thyl-1-(2'-carboxybiphenyl-4-ylmethyl)-1,2-dihydrc-2-oxopyridine i5 obtain~d afte~ conventional ~orking-up.
Example 11 A mixture of 47Z mg of 3-tert.-butoxy-carbonylaminomethyl-6-butyl-1-(2'-cyanobi-30 phenyl-4-ylmet.hyl)-1,2-dihydro-2-oxopyridine, 206 mg of trLmethyltin azide a~d 12 ml of xylene i5 boiled for 96 hours; a further 0.2 g of azide is added after 48 hour~.
The mixture is cooled, treated with e~hereal hydrochloric acid and evaporatedA Chromatography of the residue (silica gel; methylene chloride/methanol 95:5) yields 3-tert,butoxycarbonylaminomethyl-6-butyl-1,2-dihydro-2-oxo-~ etraæol-5-yl~-biphenyl-4-ylmethy ~pyridine; m.p.105.
The corresponding K salt is prepared therefrom in conven-tional manner.
2 ~ 7 ~
Exampl~ 12 6-Butyl-1,2-dihydro-2-oxo-3-ttetra~ol-5-yl)-l-f2'-~tetraz~l-5-yl)biphenyl-4-ylmethy ~pyridine, m.p. ~59 (dec.), Rf 0.1 (7:3), is obtained from 6-butyl-3-cyano-1-(2'-cyan~biphenyl-4-ylmethyl)-1,2-dihy-dro-2-oxopyridine analogously to Example 11, except that 2 equivalents of trimethyltin a~ide are used.
Dipotassium salt, m.p. 235~.
6-Butyl-3-cyano-1,2-dihydro-2-oxo-1- ~ '-(tetrazol-5-yl)biphenyl-4-ylmethyl7pyridine is cbtained as a by-product (separable by chromatography).
6-~ethyl-l,2-dihydro-2-oxo-5-propyl-3-(tetrazol-~-yl)-l-~ 2 ' - ( tetra zol - 5 -yl )biphenyl-4-ylmethyl~pyridine can be prepared analogously from 3-oyano-l-(2'-cyano-biphenyl-4-ylmethyl)-6-methyl-l,2-dihydro-2-oxo-5-propyl-pyridine.
Example 13 A mixture o 472 mg of 3-tert~-butoxy-carbonyl_ amino~ethyl-6-butyl-1-(2'-cyanGbiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridi~, 700 mg of NH~Cl, 700 mg of NaN3 and 4 ml of D~Y is stirred for 36 hours at 120. It is cooled, the NaCl formed is filtered off and the filtrate is evaporated and worked up with aqueous hydrochloric acid/methylene chloride in conven-tional manner to give 6-butyl-l,2-dihydro-2-oxo- l-[2'-~ tetrazol-5-yl)biphenyl 4-ylmethyl~pyridine, m.p. 105.
Example 14 a) A solution of l g of 6-butyl~l-(2'-nitrobiphenyl-4-ylmethyl)-1,2 dih~dro-2-oxopyridi~e in 30 ml of ethanol 3~ is hydrogenated on l g of Raney Ni at 20~ until the uptake of H2 has ceased. The mixture is filtered and evaporated to give l-(2'-aminobiphenyl-4-ylmethyl~
butyl-l,2-dihydro-2-oxopyridine.
~rl7 D.L ~
~1 A solution of 2.82 g of trifluoromethanesulfonic anhydride in 10 ml of CH2C12 is added dropwise to a solution of 3.32 g of l-(2~-aminobiphenyl-4-ylmethyl)-6 butyl-1,2-dihydro-2-oxopyridine and 1,01 g of triethyl-amine in 30 ml of CH2Cl2 at -50 to -60. The mixture is left to warm up to 20 and poured into dilute acetic acid to give 6-butyl-1-(2'-trifluoromethanesulfonamidobi-phenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine after conventional working-up.
10 Example 15 15 mg of Na~4 are added at 20 to a solution of 370 mg of 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-3 formyl-1,2-dihydro-2-oxopyridine in 5 ml of isopropa~
nol, with stirring. After further tirring (1 hour), 15 dilute hydrochloric acid is a~ded dropwi~e until the evolution of Hz ha~ cea~ed, and the mixture i~ evaporated.
6-Butyl-1-(2' cyanobiphenyl-4-ylmethyl)-3-hydroxy~ethyl-1,2-dihydro-2-oxopyridine i~ obtained after conventional working-up.
20 Example 16 0.07 ml of bromine is added dropwis at 0~ to a solution of 280 mg of NaOH in 6 ml of water, with stirring. 360 mg of 6-butyl-3-carbamoyl-1-(2~-cyano-biphenyl-4-ylmethyl)-1,2-dihydro~2-oxopyridine are then 25 added. The mixture i5 heated for 3 hour~ on a steam bath, acidified with 6 N hydrochloric acid and stirred for a further 30 minutes. It i~ neutrali~ed with 10% RHC03 solution, cooled and worked up in conventional manner to give 3-amino-6-buty~ (2~-cyanobiphenyl-4- ylmethyl) 30 1,2-dihydro-2-oxopyridine.
Example 17 A solution of 1 g of 3-~ert-butoxycarbonylamino-6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl~-1,2-dihydro-2-oxopyridine in 2a ml of a 4 N HCl solution in dioxane i5 stirred for 1 hour a~ 20 and then evaporated to give 3-amino-6-butyl~ 2'~cyanobiphenyl-4-ylmethyl)-1,2-dLhydro-2-oxopyridine in the form of the hydrochloride.
2 0 7 ~
- 33 ~
E~ample 1B
A suspension of 370~mg of 6-butyl~ 2'-cyano~
biphenyl-4-ylmethyl)-3-formyl-1,2-dihydro-2-oxopyridine, 770 mg of ammonium acetate, 61 mg of NaBH3CN and 400 mg of S a powdered 3 ~ molecular sieve in lO ml o isopropanol i~
stirred under argon for 3 days at 20. It is filtered, the material on the filter is washed with methanol and the filtrate is evaporated. 3-Aminomethyl-6-butyl~1-(2'-cyanobiphenyl-4-ylmethyl)-l,2-dihydro-2-oxopyridine is obtained after conventional working-up (sodium hydroxide solution/methylene chloride), m.p. 118.
3-~nome~yl-6-butyl-1,2~hydro-2-oxo~ '-(tetra-zol-5-yl)biph2nyl-4-ylmethyl]pyridine i~ obtained ana-logously from 6-butyl-3-formyl-l,2-dihydro-2-oxo-l-[2'-(tetrazol-5~yl)biphenyl-4-ylmethyl]pyridine, decom~ition starting at 7S.
E~ample l9 A mixture of 3.7 g of 6-butyl-l-(2'-cyanobi-phenyl-4-ylmethyl)-3- f or~yl~ dihydro-2-oxopyridine, 0.59 g of isopropylamine and 3.55 g of titanium tetra-isopropoxide is c~irred for 2 hours at 20 under N2.
10 ~1 of absolute ethanol and the~ 6lO mg of NasH3CN are added, ths ~ixture is stirred for a further 20 hours, 2 ml of water are then added and ~he mixture is filtered.
The filtrate i~ evaporated. 6-Butyl-l-(2'-cyanobiphenyl-- 4-yl~ethyl)-3-i~opropylaminomethyl-l,2-dihydro-2-oxo-pyridine is obtained after conven~ional working-up.
The following are ob~ained analogously with butylamine or benzylamine:
6-butyl-3-butylaminomethy~ (2~-cyanobiphenyl-4 ylme~hyl)-l,2-dihydro 2-oxopyridine 3-benzylaminomethyl-6-butyl-l-t2~-cyanobiphenyl-4-ylmethyl~-l,2-dihydro-2-oxopyridine, oil, Rf 0.15 (dichloromet:hane/methanol 95:5) and the following are obtained from 6-butyl-3-formyl-l-[2'-(tetrazol-5-yl)biphenyl-4-ylmethyl]-l,2-dihydro-2-2~7~:~2 ~ 34 -oxopyridine:
5-butyl-3-i~opropyl~minomethyl-1-[2~-(tetrazol-5-yl)biphenyl-4-ylmethyl3-1,2-dihydro-2-oxopyridine 6-butyl-3-butylaminomethyl-1-[2'-(tetrazol~5-yl)-biphenyl-4-ylmethyl3-1,2-dihydro-2-oxopyridine 3-benzylaminomethyl-6-butyl-1-[2'-(t~trazol-5-yl)biphenyl-4-ylmethyl]-1,2-dihydro-2-oxopyridine.
Example 20 6-Butyl~ 2'-~yanobiphenyl-4-ylmethyl)-3-iso-propylamino-1,2-dihydro-2-oxopyridine is obtained ana-logously to Example 19 from 3-~ino-6-butyl-1-(2'-c~anobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine and acetone/tita~ium tetraisopxopoxide/NaB~3CN.
The following are obtained analogously with butyraldehyde, ben~aldehyde or hexafluoroacetone from the corresponding 3-amino or 3-aminomethyl compounds:
6-butyl-3-butylamino-1-(2'-cyanobiphenyl-4 yl-mathyl~-1,2-dihydro-2-oxopyridine 3-benzylamino~6-butyl-1-(2'-cyanobiphenyl-4-yl methyl) 1,2-dihydro-~-oxopyridine 6-butyl-3~ 1,3,3,3-hexafluoro-2-propyl~mino)-1-12'~cy~nobiphenyl-4-ylmethyl)~l, 2 -dihydro-2 -oxopyridine 6-butyl-3-(1,1,1,3,3,3-hexafluoro-2-propyla~ino-m~thyl)-1-(2~-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-o~opyridine 3-benzylamino-6-butyl-1,2-dihydro-2-oxo-1-[2'-(tetrazol-5-yl)biphenyl-4-ylmethyl]pyridine 6-butyl-3-(1,1,1,3,3,3-hexafluoro-2-propylamino)-1,2-dihydro-2-oxo-1-[2'-(tetra~ol-5-yl)biphenyl-4-ylmethyl3pyridine 6-butyl-3-(1,1,1/3,3,3-hexafluoro-2-propylamino-methyl)-1,2-dihydro-2-oxo-1-[2'-(tetrazol-5-yl)-biphenyl~4-ylmethyl]pyridine.
2~77~ ~
~xample 21 Analogously to Example 1, there are obtained from IIa with 6-butyl-1.2-dihydro-3-methyl~ulfonylaminomethyl-, -3-trifluorom~thyl-sulfonylaminomethyl-, -3-phenyl~ulfonyla~inomethyl- ~r -3-p-t~lyi-sulfonylaminomethyl-2-oxo-pyridine the follo~ing 6-butyl~ '-oyano-biphenyl-4-yl~-methyl-1,2-dihydro-2-oxo-pyridines:
3-methylsulfonylaminomethyl-, m p 59 3-trifluoromethyl~ulfonylaminomethyl-~-phenylsulfonylaminomethyl-3-p-tolylsulfonylaminomethyl-, m p.119 Example 22 Analogously to Example 11, the following 6-butyl-1-[2'-(~-tetrazolyl)-biphenylyl-4-~ethyl~-1,2-dihydro-2-oxo-pyridines are obtained from the 2'cyano-biphenyl-4-yl compounds mentioned in Example 21 ~ith trir~ethyltin azide:
3-methylsulfonylaminomethyl-3-trifluoron~thylsulfonylaminomethyl-3-phenylsulfonylaminomethyl-3-p-tolylsulfonylamino~ethyl-.
2 ~1 7 7 ~ 1 r~
The following Example~ relate to pharmaceutical formulations containing active ingredients of formula I
or their salts.
Example A: Tablets and coated tablets Tablets of the following compo~ition are produced by pressing in conventional manner and, where necessary, are provided with a conventional ~ucrose- based coating:
Active ingredient of formula I100 mg 10 Microcrystalline cellulose278.8 mg Lactose 110 mg Maize ~tarch ll mg Magnesium steara~ 5 mg Finely divided silicon dioxido0.2 ~q Example E: ~ rd gelatin cap~ul~
Conventional two-part hard gel~tin capsules are each filled with Active ingredient of formula I100 mg Lactose 150 mg 20 Cellulose 50 mg Magn~sium ~tearate S mg ~xample C: Soft gelatin capcule~
Conventional soft gelatin capsule~ are filled with a mixture consisting in each case of 50 mq of active ingredient of formula I and 250 mg of olive oil.
Example D: Ampoules A solution of 200 g of active ingredient of formula I in 2 kg of propane-1,2-diol is made up to 10 1 ~ith water and filled into ampoule~ 80 that each ampoule contains 20 mg of active ingredient.
Claims (8)
1. 1,2-Dihydro-2-oxopyridines of formula I
I
in which R is the radical , R1 is H, Hal, A, OA or NO2, R2 is COOH, COOA, CN, NO2, NH2, NHCOR7, NHSO2R7 or tetrazol 5-yl, R3 is H, COOH, COOA, CHO, CN, NO2, CH2R8, CH2OR9, NR10R11 CH2NR10R11, CONR10R11 or tetrazol-5-yl, R4 is H or A, R5, R6 and R10 are in each case H, A, alkenyl having 2-6 C
atoms, alkynyl having 2-6 C atoms, Ar or Ar-alkyl having 1-6 C atoms in the "alkyl" moiety, R7 is A or A monosubstituted or polysubstituted by F, R8 is H, Hal, A, Ar, CN, COOH, COOA, CH2COOH, CH2COOA
or tetrazol-5-yl, R9 is H, A, Ar, Ar-alkyl having 1-6 C atoms in the "alkyl" moiety, COA, COAr, COOA, COORr, CONR12R13, COO-alkyl-Ar or A-O-alkyl having 1-6 C atoms in the "alkyl" moiety in each case, R11 H, A, A monosubstituted or polysubstituted by F, Ar, Ar-alkyl having 1 6 C atoms in the "alkyl"
moiety, CO-A, CO-Ar, CO-alkyl-Ar having 1-6 C
atoms in the "alkyl" moiety, COOA, COOAr, COO-alkyl-Ar having 1-6 C atoms in the "alkyl"
moiety, or CONR12R13, NR10R11 is also pyrrolidino, piperidino, morpholino, succinimido or phthalimido, R12 and R13 are in each case H, A, cycloalkyl having 3-8 C
atoms, alkenyl having 2-6 C atoms, alkynyl having
I
in which R is the radical , R1 is H, Hal, A, OA or NO2, R2 is COOH, COOA, CN, NO2, NH2, NHCOR7, NHSO2R7 or tetrazol 5-yl, R3 is H, COOH, COOA, CHO, CN, NO2, CH2R8, CH2OR9, NR10R11 CH2NR10R11, CONR10R11 or tetrazol-5-yl, R4 is H or A, R5, R6 and R10 are in each case H, A, alkenyl having 2-6 C
atoms, alkynyl having 2-6 C atoms, Ar or Ar-alkyl having 1-6 C atoms in the "alkyl" moiety, R7 is A or A monosubstituted or polysubstituted by F, R8 is H, Hal, A, Ar, CN, COOH, COOA, CH2COOH, CH2COOA
or tetrazol-5-yl, R9 is H, A, Ar, Ar-alkyl having 1-6 C atoms in the "alkyl" moiety, COA, COAr, COOA, COORr, CONR12R13, COO-alkyl-Ar or A-O-alkyl having 1-6 C atoms in the "alkyl" moiety in each case, R11 H, A, A monosubstituted or polysubstituted by F, Ar, Ar-alkyl having 1 6 C atoms in the "alkyl"
moiety, CO-A, CO-Ar, CO-alkyl-Ar having 1-6 C
atoms in the "alkyl" moiety, COOA, COOAr, COO-alkyl-Ar having 1-6 C atoms in the "alkyl"
moiety, or CONR12R13, NR10R11 is also pyrrolidino, piperidino, morpholino, succinimido or phthalimido, R12 and R13 are in each case H, A, cycloalkyl having 3-8 C
atoms, alkenyl having 2-6 C atoms, alkynyl having
2-6 C atoms, or Ar, X is absent or is -CO-, -O-, -NH-CO-, -CO-NH-, -CH2-O- or -O-CH2-, A is alkyl having 1-6 C atoms, Ar is phenyl which is unsubstituted or monosub-stituted by A, OA, CF3, Hal or NO2, and Hal is F, Cl, Br or I, wherein, however, at least one of the following provisos must be met:
(a) R1 is Hal, A, OA or NO2;
(b) R2 is CN, NO2, NH2, NHCOR7 or NHSO2R7;
(c) R3 is CH2Ar, CH2CH, CH2COOH, CH2COOA, CH2CH2COOH, CH2CH2COOAr, CH2-(tetrazol-5-yl);
CH2OAr, CH2O-alkyl-Ar' (wherein Ar' is a phenyl group monosubstituted by A, OA, CF3, Hal or NO2), CH2O-CO-Ar', CH2OCOOA , CH2OCONR14R15, (wherein R14 and R15, independently from each other, are alkenyl, alkinyl or Ar, one of R14 and R15 can also be H or A), CH2O-COO-alkyl-Ar, CH2O-alkyl-O-A;
NR16R17 (wherein R16 is alkenyl, alkinyl, Ar or Ar-alkyl, R17 is A monosubstituted or polysubstituted by F, Ar, Ar-alkyl, CO-Ar, CO-alkyl-Ar, COOA, COOAr, COO-alkyl-Ar or CONR12R13, one of R16 and R17 can also be H or A), pyrrolidino, piperidino, morpholino, succinimido, phthalimido;
CH2NR10R11;
CONR18R19 (wherein R18 is alkenyl, alkinyl, Ar or AR-alkyl, R19 is A monosubstituted or polysubstituted by F, Ar'. Ar-alkyl, CO-Ar, CO-alkylAr, COOA, COOAr, COO-alkyl-Ar or CONR12R13, one of R18 and R19 can also be H or A, the group NR18 R19 can also be succinimido or phthalimido);
(d) R5 is alkinyl, Ar' or Ar-alkyl;
(e) R8 is alkinyl, Ar' or Ar-alkyl;
(f) X is -CO-, -O-, -NH-CO-, -CO-NH-, -CH2-O- or -O-CH2-, and their salts.
2. a) 6-Butyl-1,2-dihydro-2-oxo-1-[2'-(tetrazol-5-yl)biphenyl-4-ylmethyl]pyridine.
b) 6-Butyl-1,2-dihydro-2-oxo-3-(tetrazol-5-yl)-
(a) R1 is Hal, A, OA or NO2;
(b) R2 is CN, NO2, NH2, NHCOR7 or NHSO2R7;
(c) R3 is CH2Ar, CH2CH, CH2COOH, CH2COOA, CH2CH2COOH, CH2CH2COOAr, CH2-(tetrazol-5-yl);
CH2OAr, CH2O-alkyl-Ar' (wherein Ar' is a phenyl group monosubstituted by A, OA, CF3, Hal or NO2), CH2O-CO-Ar', CH2OCOOA , CH2OCONR14R15, (wherein R14 and R15, independently from each other, are alkenyl, alkinyl or Ar, one of R14 and R15 can also be H or A), CH2O-COO-alkyl-Ar, CH2O-alkyl-O-A;
NR16R17 (wherein R16 is alkenyl, alkinyl, Ar or Ar-alkyl, R17 is A monosubstituted or polysubstituted by F, Ar, Ar-alkyl, CO-Ar, CO-alkyl-Ar, COOA, COOAr, COO-alkyl-Ar or CONR12R13, one of R16 and R17 can also be H or A), pyrrolidino, piperidino, morpholino, succinimido, phthalimido;
CH2NR10R11;
CONR18R19 (wherein R18 is alkenyl, alkinyl, Ar or AR-alkyl, R19 is A monosubstituted or polysubstituted by F, Ar'. Ar-alkyl, CO-Ar, CO-alkylAr, COOA, COOAr, COO-alkyl-Ar or CONR12R13, one of R18 and R19 can also be H or A, the group NR18 R19 can also be succinimido or phthalimido);
(d) R5 is alkinyl, Ar' or Ar-alkyl;
(e) R8 is alkinyl, Ar' or Ar-alkyl;
(f) X is -CO-, -O-, -NH-CO-, -CO-NH-, -CH2-O- or -O-CH2-, and their salts.
2. a) 6-Butyl-1,2-dihydro-2-oxo-1-[2'-(tetrazol-5-yl)biphenyl-4-ylmethyl]pyridine.
b) 6-Butyl-1,2-dihydro-2-oxo-3-(tetrazol-5-yl)-
3. Process for the preparation of 1,2-dihydro-2-oxopyridines of formula I according to Claim 1, and their salts, characterised in that (a) a compound of formula II:
II
in which E is Cl, Br, I, a free OH group or an OH group which has been functionally modified to acquire reactivity, and R1, R2 and X are as defined in Claim 1, is reacted with a compound of formula III:
H-R III
in which R is as defined in Claim 1, or (b) to prepare a compound of formula I in which X is -NH-CO- or -CO-NH-, a compound of formula IV:
IV
in which X1 is NH2 or COOH and R is as defined in Claim 1, or a reactive derivative of this compound, is reacted with a compoun of formula V:
V
in which X2 is COOH (if X1 is NH2) or NH2 (if X1 is COOH) and R1 and R2 are as defined in Claim 1, or with a reactive derivative of this compound, or (c) to prepare a compound of formula I in which X is -CH2-O- or -O-CH2-, a compound of formula VI:
VI
in which X3 is CH2E or OH and R is as defined in Claim 1, or a reactive derivative of this compound, is reacted with a compound of formula VII:
VII
in which X4 is OH (if X3 is CH2E) or CH2E (if X3 is OH) and R1 and R2 are as defined in Claim 1, or with a reactive derivative of this compound, or in that a compound of formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent, and/or in that one or more radicals R1, R2, R3, R4, R5 and/or R6 in a compound of formula I are converted to one or more other radicals R1, R2, R3, R4, R5 and/or R6, and/or a base or acid of formula I is converted to one of its salts.
II
in which E is Cl, Br, I, a free OH group or an OH group which has been functionally modified to acquire reactivity, and R1, R2 and X are as defined in Claim 1, is reacted with a compound of formula III:
H-R III
in which R is as defined in Claim 1, or (b) to prepare a compound of formula I in which X is -NH-CO- or -CO-NH-, a compound of formula IV:
IV
in which X1 is NH2 or COOH and R is as defined in Claim 1, or a reactive derivative of this compound, is reacted with a compoun of formula V:
V
in which X2 is COOH (if X1 is NH2) or NH2 (if X1 is COOH) and R1 and R2 are as defined in Claim 1, or with a reactive derivative of this compound, or (c) to prepare a compound of formula I in which X is -CH2-O- or -O-CH2-, a compound of formula VI:
VI
in which X3 is CH2E or OH and R is as defined in Claim 1, or a reactive derivative of this compound, is reacted with a compound of formula VII:
VII
in which X4 is OH (if X3 is CH2E) or CH2E (if X3 is OH) and R1 and R2 are as defined in Claim 1, or with a reactive derivative of this compound, or in that a compound of formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent, and/or in that one or more radicals R1, R2, R3, R4, R5 and/or R6 in a compound of formula I are converted to one or more other radicals R1, R2, R3, R4, R5 and/or R6, and/or a base or acid of formula I is converted to one of its salts.
4. Process for the preparation of pharmaceutical formulations, characterised in that a compound of formula I according to Claim 1, and/or one of its physiologically acceptable acid addition salts, are incorporated into a suitable dosage form together with at least one solid, liquid or semiliquid excipient or adjunct.
5. Pharmaceutical formulation, characterised in that it contains at least one compound of formula I according to Claim 1, and/or one of its physiologically acceptable acid addition salts.
6. Compounds of formula I according to Claim 1, and their physiologically acceptable acid addition salts, for controlling diseases.
7. Use of compounds of formula I according to Claim 1, and/or their physiologically acceptable acid addition salts, for the preparation of a drug.
8. Use of compounds of formula I according to Claim 1, and/or their physiologically acceptable acid addition salts, in controlling diseases.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4129340A DE4129340A1 (en) | 1991-09-04 | 1991-09-04 | 1,2-dihydro-2-OXOPYRIDINE |
| DEP4129340.1 | 1991-09-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2077412A1 true CA2077412A1 (en) | 1993-03-05 |
Family
ID=6439801
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002077412A Abandoned CA2077412A1 (en) | 1991-09-04 | 1992-09-02 | 1,2-dihydro-2-oxopyridines |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0530702A1 (en) |
| JP (1) | JPH05194397A (en) |
| KR (1) | KR930005980A (en) |
| AU (1) | AU660321B2 (en) |
| CA (1) | CA2077412A1 (en) |
| CZ (1) | CZ263592A3 (en) |
| DE (1) | DE4129340A1 (en) |
| HU (1) | HUT64520A (en) |
| MX (1) | MX9205032A (en) |
| NO (1) | NO923434L (en) |
| PL (1) | PL295811A2 (en) |
| RU (1) | RU2067975C1 (en) |
| TW (1) | TW218010B (en) |
| ZA (1) | ZA926733B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7998986B2 (en) | 2001-12-21 | 2011-08-16 | Exelixis Patent Company Llc | Modulators of LXR |
| US8013001B2 (en) | 2001-12-21 | 2011-09-06 | Exelixis, Inc. | Modulators of LXR |
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4221583A1 (en) | 1991-11-12 | 1993-05-13 | Bayer Ag | SUBSTITUTED BIPHENYLPYRIDONE |
| DE4215588A1 (en) * | 1992-05-12 | 1993-11-18 | Bayer Ag | Biphenylmethyl-substituted pyridones |
| DE69301867T2 (en) * | 1992-06-16 | 1996-10-02 | Agfa Gevaert Nv | X-ray screen |
| DE4309552A1 (en) * | 1993-03-24 | 1994-09-29 | Bayer Ag | Substituted nitrogen heterocycles |
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| DE4316077A1 (en) * | 1993-05-13 | 1994-11-17 | Bayer Ag | Substituted mono- and bihydridylmethylpyridones |
| DE4334308A1 (en) * | 1993-10-08 | 1995-04-13 | Merck Patent Gmbh | 1,2-dihydro-2-oxo-3-pyridine-methylsulfonylaminomethyl |
| DE4336051A1 (en) * | 1993-10-22 | 1995-04-27 | Merck Patent Gmbh | 1,2-Dihydro-2-oxopyridines |
| KR100327273B1 (en) * | 1994-04-08 | 2002-05-10 | 고사이 아끼오 | Ether compound, use thereof, and intermediate for producing the compound |
| CN1043041C (en) * | 1994-04-22 | 1999-04-21 | 住友化学工业株式会社 | Ether compound and use thereof |
| DE19830431A1 (en) | 1998-07-08 | 2000-01-13 | Hoechst Marion Roussel De Gmbh | Sulfonylamino-carboxylic acid N-arylamides as guanylate cyclase activators |
| AR059898A1 (en) | 2006-03-15 | 2008-05-07 | Janssen Pharmaceutica Nv | DERIVATIVES OF 3-CIANO-PIRIDONA 1,4-DISUSTITUTED AND ITS USE AS ALLOSTERIC MODULATORS OF MGLUR2 RECEIVERS |
| TW200845978A (en) | 2007-03-07 | 2008-12-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives |
| TW200900065A (en) | 2007-03-07 | 2009-01-01 | Janssen Pharmaceutica Nv | 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives |
| EP2998314B1 (en) | 2007-06-04 | 2020-01-22 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| TWI475995B (en) | 2007-09-14 | 2015-03-11 | Janssen Pharmaceuticals Inc | 1',3'-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2h, 1'h-[1,4'] bipyridinyl-2'-ones |
| EP3239170B1 (en) | 2008-06-04 | 2019-03-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| WO2010009319A2 (en) | 2008-07-16 | 2010-01-21 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
| EP2344470B1 (en) | 2008-09-02 | 2013-11-06 | Janssen Pharmaceuticals, Inc. | 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors |
| CA2744138C (en) | 2008-11-28 | 2015-08-11 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc. | Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors |
| MY153913A (en) | 2009-05-12 | 2015-04-15 | Janssen Pharmaceuticals Inc | 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
| AU2010246607B2 (en) | 2009-05-12 | 2012-09-27 | Addex Pharma S.A. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors |
| JO2907B1 (en) | 2009-05-12 | 2015-09-15 | اديكس فرما اس ايه | 1,2,4TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| EP2643320B1 (en) | 2010-11-08 | 2015-03-04 | Janssen Pharmaceuticals, Inc. | 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS |
| JP5852666B2 (en) | 2010-11-08 | 2016-02-03 | ジヤンセン・フアーマシユーチカルズ・インコーポレーテツド | 1,2,4-Triazolo [4,3-a] pyridine derivatives and their use as positive allosteric modulators of the mGluR2 receptor |
| CA2814996C (en) | 2010-11-08 | 2019-10-01 | Janssen Pharmaceuticals, Inc. | 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors |
| CA2905438A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| CA2905435A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| JO3368B1 (en) | 2013-06-04 | 2019-03-13 | Janssen Pharmaceutica Nv | 6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZIN-4(5H)-ONE COMPOUNDS AND THEIR USE AS NEGATIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS |
| AU2014274812B2 (en) | 2013-06-05 | 2018-09-27 | Bausch Health Ireland Limited | Ultra-pure agonists of guanylate cyclase C, method of making and using same |
| JO3367B1 (en) | 2013-09-06 | 2019-03-13 | Janssen Pharmaceutica Nv | 1,2,4-TRIAZOLO[4,3-a]PYRIDINE COMPOUNDS AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS |
| CN109999025A (en) | 2014-01-21 | 2019-07-12 | 詹森药业有限公司 | Positive allosteric modulator or the combination of normotopia agonist including metabotropic glutamate energy receptor subtype 2 and application thereof |
| IL279202B2 (en) | 2014-01-21 | 2023-09-01 | Janssen Pharmaceutica Nv | Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880804A (en) * | 1988-01-07 | 1989-11-14 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking benzimidazoles |
| CA2037630C (en) * | 1990-03-07 | 2001-07-03 | Akira Morimoto | Nitrogen-containing heterocylic compounds, their production and use |
| EP0487745A4 (en) * | 1990-06-19 | 1993-01-20 | Meiji Seika Kabushiki Kaisha | Pyridine derivative with angiotensin ii antagonism |
| IL100917A0 (en) * | 1991-02-16 | 1992-11-15 | Fisons Plc | Pyridinone and pyrimidinone derivatives,their preparation and pharmaceutical compositions containing them |
| DE4221583A1 (en) * | 1991-11-12 | 1993-05-13 | Bayer Ag | SUBSTITUTED BIPHENYLPYRIDONE |
-
1991
- 1991-09-04 DE DE4129340A patent/DE4129340A1/en not_active Withdrawn
-
1992
- 1992-08-26 CZ CS922635A patent/CZ263592A3/en unknown
- 1992-08-28 EP EP92114738A patent/EP0530702A1/en not_active Ceased
- 1992-09-01 AU AU22055/92A patent/AU660321B2/en not_active Ceased
- 1992-09-02 TW TW081106953A patent/TW218010B/zh active
- 1992-09-02 PL PL29581192A patent/PL295811A2/en unknown
- 1992-09-02 MX MX9205032A patent/MX9205032A/en unknown
- 1992-09-02 CA CA002077412A patent/CA2077412A1/en not_active Abandoned
- 1992-09-03 NO NO92923434A patent/NO923434L/en unknown
- 1992-09-03 KR KR1019920016029A patent/KR930005980A/en not_active Application Discontinuation
- 1992-09-03 RU SU925052529A patent/RU2067975C1/en active
- 1992-09-04 JP JP4237202A patent/JPH05194397A/en active Pending
- 1992-09-04 HU HU9202848A patent/HUT64520A/en unknown
- 1992-09-04 ZA ZA926733A patent/ZA926733B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7998986B2 (en) | 2001-12-21 | 2011-08-16 | Exelixis Patent Company Llc | Modulators of LXR |
| US8013001B2 (en) | 2001-12-21 | 2011-09-06 | Exelixis, Inc. | Modulators of LXR |
Also Published As
| Publication number | Publication date |
|---|---|
| NO923434L (en) | 1993-03-05 |
| JPH05194397A (en) | 1993-08-03 |
| HU9202848D0 (en) | 1992-11-30 |
| ZA926733B (en) | 1993-03-10 |
| AU660321B2 (en) | 1995-06-22 |
| NO923434D0 (en) | 1992-09-03 |
| RU2067975C1 (en) | 1996-10-20 |
| DE4129340A1 (en) | 1993-03-11 |
| PL295811A2 (en) | 1993-05-04 |
| CZ263592A3 (en) | 1993-03-17 |
| EP0530702A1 (en) | 1993-03-10 |
| AU2205592A (en) | 1993-03-11 |
| TW218010B (en) | 1993-12-21 |
| HUT64520A (en) | 1994-01-28 |
| MX9205032A (en) | 1993-05-01 |
| KR930005980A (en) | 1993-04-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |